COMPOUNDS COMPRISING A FIBROBLAST ACTIVATION PROTEIN LIGAND AND USE THEREOF

Abstract

The present invention is related to a compound comprising a cyclic peptide

of formula (I)

##STR00001##

and an N-terminal modification group A attached to Xaa1,
wherein
each and any one of Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa6 and Xaa7 is a residue of an amino acid, and
Yc is a structure of formula (X)

##STR00002##

Claims

1. A compound comprising a cyclic peptide of formula (I) ##STR00366## and an N-terminal modification group A attached to Xaa1, wherein the peptide sequence is drawn from left to right in N to C-terminal direction, Xaa1 is a residue of an amino acid of formula (II) ##STR00367## wherein R.sup.1a is —NH— R.sup.1b is H or CH.sub.3, n=0 or 1, the N-terminal modification group A is covalently attached to the nitrogen atom of Xaa1, the carbonyl group of Xaa1 is covalently attached to the nitrogen of Xaa2, and the sulfur atom of Xaa1 is covalently attached as thioether to Yc; Xaa2 is a residue of an amino acid of formula (III), (IV) or (XX) ##STR00368## wherein R.sup.2a, R.sup.2b, R.sup.2c are each and independently selected from the group consisting of(C.sub.1-C.sub.2)alkyl and H, wherein said (C.sub.1-C.sub.2)alkyl may be substituted by a substituent selected from the group consisting of OH, NH.sub.2, halogen, (C.sub.5-C.sub.7)cycloalkyl, p=0, 1 or 2 v=1 or 2 w=1, 2 or 3 and the amino acid of formula (IV) may be substituted by one or two substituents selected from the group consisting of methyl, OH, NH.sub.2 and F at indicated ring positions 3 and 4; Xaa3 is a residue of an amino acid of formula (V) or (XX) ##STR00369## wherein X.sup.3 is selected from the group consisting of CH.sub.2, CF.sub.2, CH—R.sup.3b, S, O and NH, p=1 or 2 v=1 or 2 w=1, 2 or 3, R.sup.3a is H, methyl, OH, NH.sub.2 or F, R.sup.3b is methyl, OH, NH.sub.2 or F; Xaa4 is a residue of an amino acid of formula (VI) ##STR00370## wherein R.sup.4a is selected from the group consisting of H, OH, COOH, CONH.sub.2, X.sup.4 and —NH—CO—X.sup.4, wherein X.sup.4 is selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.5-C.sub.6)aryl and (C.sub.5-C.sub.6)heteroaryl, and X.sup.4 may be substituted by one or two substituents selected from the group consisting of methyl, CONH.sub.2, halogen, NH.sub.2 and OH; q=1, 2 or 3, wherein optionally one or two hydrogens of said one, two or three CH.sub.2-groups are each and individually substituted by methyl, ethyl, (C.sub.5-C.sub.6)aryl or (C.sub.5-C.sub.6)heteroaryl, R.sup.4 is methyl or H; Xaa5 is a residue of an amino acid of structure (VII) ##STR00371## wherein R.sup.5 is selected from the group of OH and NH.sub.2, and r=1, 2 or 3; Xaa6 is an amino acid selected from the group consisting of an aromatic L-α-amino acid and a heteroaromatic L-α-amino acid; Xaa7 is a residue of an amino thiol or an amino acid of formula (IX), ##STR00372## wherein R.sup.7a is —CO—, —COOH, —CONH.sub.2, —CH.sub.2—OH, —(CO)—NH—R.sup.7b, —(CO)—(NR.sup.7c)—R.sup.7b or H, wherein R.sup.7b and R.sup.7c are each and independently (C.sub.1-C.sub.4)alkyl and t is 1 or 2; Yc is a structure of formula (X) ##STR00373## linking the S atom of Xaa1 and the S atom of Xaa7 under the formation of two thioether linkages thus forming a cyclic structure of formula (XXI) ##STR00374## wherein the substitution pattern of the aromatic group in formula (X) is ortho, meta or para, n=0 or 1, t=1 or 2, Y.sup.1 is C—H or N, Y.sup.2 is N or C—R.sup.c1, R.sup.c1 is H or CH.sub.2—R.sup.c2 and R.sup.c2 is a structure of formula (XI), (XII) or (XXII) ##STR00375## wherein R.sup.c3 and R.sup.c4 are each and independently selected from the group consisting of H and (C.sub.1-C.sub.4)alkyl and u=1, 2, 3, 4, 5 or 6, x and y are each and independently 1, 2 or 3, and X=O or S, wherein in formulae (XI) and (XXII) one of the nitrogen atoms is attached to —CH.sub.2— of R.sup.c1 and in formula (XII) —X— is attached to —CH.sub.2— of R.sup.c1; and wherein the N-terminal modification group A is either a blocking group Abl or an amino acid Aaa.

2. A compound comprising a cyclic peptide of formula (I) ##STR00376## and an N-terminal modification group A attached to Xaa1, wherein the peptide sequence is drawn from left to right in N to C-terminal direction, Xaa1 is a residue of an amino acid of formula (II) ##STR00377## wherein R.sup.1a is —NH— R.sup.1b is H or CH.sub.3, n=0 or 1, the N-terminal modification group A is covalently attached to the nitrogen atom of Xaa1, the carbonyl group of Xaa1 is covalently attached to the nitrogen of Xaa2, and the sulfur atom of Xaa1 is covalently attached as thioether to Yc; Xaa2 is a residue of an amino acid of formula (III), (IV) or (XX) ##STR00378## wherein R.sup.2a, R.sup.2b, R.sup.2c are each and independently selected from the group consisting of (C.sub.1-C.sub.2)alkyl and H, wherein said (C.sub.1-C.sub.2)alkyl may be substituted by a substituent selected from the group consisting of OH, NH.sub.2, halogen, (C.sub.5-C.sub.7)cycloalkyl, p=0, 1 or 2 v=1 or 2 w=1, 2 or 3 and the amino acid of formula (IV) may be substituted by one or two substituents selected from the group consisting of methyl, OH, NH.sub.2 and F at indicated ring positions 3 and 4; Xaa3 is a residue of an amino acid of formula (V) or (XX) ##STR00379## wherein X.sup.3 is selected from the group consisting of CH.sub.2, CF.sub.2, CH—R.sup.3b, S, O and NH, p=1 or 2 v=1 or 2 w=1, 2 or 3, R.sup.3a is H, methyl, OH, NH.sub.2 or F, R.sup.3b is methyl, OH, NH.sub.2 or F; Xaa4 is a residue of an amino acid of formula (VI) ##STR00380## wherein R.sup.4a is selected from the group consisting of H, OH, COOH, CONH.sub.2, X.sup.4 and —NH—CO— X.sup.4, wherein X.sup.4 is selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.5-C.sub.6)aryl and (C.sub.5-C.sub.6)heteroaryl, and X.sup.4 may be substituted by one or two substituents selected from the group consisting of methyl, CONH.sub.2, halogen, NH.sub.2 and OH; q=1, 2 or 3, wherein optionally one or two hydrogens of said one, two or three CH.sub.2-groups are each and individually substituted by methyl, ethyl, (C.sub.5-C.sub.6)aryl or (C.sub.5-C.sub.6)heteroaryl, R.sup.4b is methyl or H; Xaa5 is a residue of an amino acid of structure (VII) ##STR00381## wherein R.sup.5 is selected from the group of OH and NH.sub.2, and r=1, 2 or 3; Xaa6 is an amino acid selected from the group consisting of an aromatic L-α-amino acid and a heteroaromatic L-α-amino acid; Xaa7 is a residue of an amino thiol or an amino acid of formula (IX), ##STR00382## wherein R.sup.7a is —CO—XXX, —COOH, —CONH.sub.2, —CH.sub.2—OH, —(CO)—NH—R.sup.7b, —(CO)—(NR.sup.7c)—R.sup.7b or H, wherein XXX is an amino acid or a peptide which forms an amide bond to the carbonyl carbon atom, wherein R.sup.7b and R.sup.7c are each and independently (C.sub.1-C.sub.4)alkyl, wherein the amino acid or the peptide is optionally substituted by a Z group, and t is 1 or 2; Yc is a structure of formula (X) ##STR00383## linking the S atom of Xaa1 and the S atom of Xaa7 under the formation of two thioether linkages thus forming a cyclic structure of formula (XXI) ##STR00384## wherein the substitution pattern of the aromatic group in formula (X) is ortho, meta or para, n=0 or 1, t=1 or 2, Y.sup.1 is C—H or N, Y.sup.2 is N or C—R.sup.c1, R.sup.c1 is H or CH.sub.2—R.sup.c2 and R.sup.c2 is a structure of formula (XI), (XII) or (XXII) ##STR00385## wherein R.sup.c3 and R.sup.c4 are each and independently selected from the group consisting of H and (C.sub.1-C.sub.4)alkyl, R.sup.c5 is H or a Z group, and u=1, 2, 3, 4, 5 or 6, x and y are each and independently 1, 2 or 3, and X=O or S wherein in formulae (XI) and (XXII) one of the nitrogen atoms is attached to —CH.sub.2— of R.sup.c1 and in formula (XII) —X— is attached to —CH.sub.2— of R.sup.c1; and wherein the N-terminal modification group A is either a blocking group Abl or an amino acid Aaa, wherein the amino acid Aaa can optionally be substituted by a Z group; and wherein each Z group comprises a chelator and optionally a linker.

3. The compound of claim 2, wherein R.sup.c5 is a Z group comprising a chelator and optionally a linker, R.sup.7a is —CO—XXX, —COOH, —CONH.sub.2, —CH.sub.2—OH, —(CO)—NH—R.sup.7b, —(CO)—(NR.sup.7c)—R.sup.7b or H, wherein R.sup.7b and R.sup.7c are each and independently (C.sub.1-C.sub.4)alkyl, XXX is an amino acid or a peptide which forms an amide bond to the carbonyl carbon atom, wherein the amino acid or the peptide is not substituted by a Z group; and if the N-terminal modification group A is an amino acid Aaa, the amino acid Aaa is not substituted by a Z group comprising a chelator and optionally a linker.

4. The compound of claim 2, wherein R.sup.7a is different from —CO—XXX, wherein XXX is an amino acid or a peptide which forms an amide bond to the carbonyl carbon atom and if the N-terminal modification group A is an amino acid Aaa, the amino acid Aaa is not substituted by a Z group comprising a chelator and optionally a linker.

5. The compound of claim 2, wherein R.sup.7a is —CO—XXX, wherein XXX is an amino acid or a peptide which forms an amide bond to the carbonyl carbon atom, wherein the amino acid or the peptide is substituted by a Z group comprising a chelator and optionally a linker, R.sup.c1 or R.sup.c5 is H, and if the N-terminal modification group A is an amino acid Aaa, the amino acid Aaa is not substituted by a Z group comprising a chelator and optionally a linker.

6. The compound of claim 2, wherein the N-terminal modification group A is amino acid Aaa substituted by a Z group comprising a chelator and optionally a linker, R.sup.c1 or R.sup.c5 is H, and R.sup.7a is —CO—XXX—COOH, —CONH.sub.2, —CH.sub.2—OH, —(CO)—NH—R.sup.7b, —(CO)—(NR.sup.7c)—R.sup.7b or H, wherein R.sup.7b and R.sup.7c are each and independently (C.sub.1-C.sub.4)alkyl, XXX is an amino acid or a peptide which forms an amide bond to the carbonyl carbon atom, wherein the amino acid or the peptide is not substituted by a Z group comprising a chelator and optionally a linker.

7. The compound of claim 6, wherein R.sup.7a is different from —CO—XXX, wherein XXX is an amino acid or a peptide which forms an amide bond to the carbonyl carbon atom.

8. The compound of claim 2, wherein the amino acid Aaa is a D-amino acid residue or an L-amino acid residue each of structure (XIV): ##STR00386## wherein R.sup.a2 is selected from the group consisting of (C.sub.1-C.sub.6)alkyl, modified (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.3)alkyl, modified (C.sub.1-C.sub.3), (C.sub.3-C.sub.8)carbocycle, aryl, heteroaryl and (C.sub.3-C.sub.8)heterocycle, wherein in modified (C.sub.1-C.sub.6)alkyl one —CH.sub.2— group is replaced by —S— or —O—, and in modified (C.sub.1-C.sub.3)alkyl one of the H is substituted by OH, F or COOH, or two of the H are substituted by F, and wherein R.sup.a3 is a Z group,

9. The compound of claim 1, where the blocking group Abl is selected from the group consisting of R.sup.a1—C(O)—, R.sup.a1—S(O.sub.2)—, R.sup.a1—NH—C(O)— and R.sup.a1—O—C(O)—; wherein R.sup.a1 is (C.sub.1-C.sub.8)alkyl optionally substituted by up to two substituents each and independently selected from the group consisting of OH, F, COOH, (C.sub.3-C.sub.8)cycloalkyl, aryl, heteroaryl and (C.sub.3-C.sub.8)heterocycle, and wherein in (C.sub.1-C.sub.8)alkyl one of the —CH.sub.2-groups is optionally replaced by —S— or —O—.

10. The compound of claim 9, wherein the blocking group Abl is hexanoyl or pentyl sulfonyl, preferably blocking group Abl is hexanoyl.

11. The compound of claim 1, wherein the amino acid Aaa is a D-amino acid residue or an L-amino acid residue each of structure (XIV): ##STR00387## wherein R.sup.a2 is selected from the group consisting of (C.sub.1-C.sub.6)alkyl, modified (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.3)alkyl, modified (C.sub.1-C.sub.3), (C.sub.3-C.sub.8)carbocycle, aryl, heteroaryl and (C.sub.3-C.sub.8)heterocycle, wherein in modified (C.sub.1-C.sub.6)alkyl one —CH.sub.2— group is replaced by —S— or —O—, and in modified (C.sub.1-C.sub.3)alkyl one of the H is substituted by OH, F or COOH, or two of the H are substituted by F, and wherein R is H or acetyl.

12. The compound of claim 1, wherein the amino acid Aaa is selected from the group consisting of the amino acid residues of Nle, nle, Met and met, and their derivatives.

13. The compound of claim 1 wherein Xaa1 is a D-amino acid residue selected from the group consisting of cys, hcy and pen, or Xaa1 is an L-amino acid residue selected from the group consisting of Cys, Hcy and Pen.

14. The compound of claim 1, wherein Xaa2 is an amino acid residue selected from the group consisting of Pro, Gly, Nmg and their derivatives, wherein Xaa3 is an amino acid residue selected from the group consisting of Pro, Hyp, Tfp, Cfp, Dmp, Aze and Pip, and their derivatives, wherein Xaa4 is an amino acid residue selected from the group consisting of Thr, Hse, Asn, Gln and Ser, and their derivatives, wherein Xaa5 is an amino acid residue selected from the group consisting of Gln and Glu, and their derivatives, wherein Xaa6 is an amino acid residue of any one of formulae (VIIIa), (VIIIb), (VIIIc) and (VIIId): ##STR00388## wherein R.sup.6a and R.sup.6b are each and independently selected from the group consisting of H, methyl, ethyl, propyl and isopropyl, R.sup.6c represents from 0 to 3 substituents, each such substituent being each and independently selected from the group consisting of Cl, F, Br, NO.sub.2, NH.sub.2, CN, CF.sub.3, OH, OR.sup.6d and C.sub.1-C.sub.4 alkyl, R.sup.6d is selected from the group consisting of methyl, ethyl, propyl, and isopropyl, and s is 0 or 1, preferably Xaa6 is an amino acid residue of any one of formulae (VIIIa), (VIIIb), (VIIIc) and (VIIId): ##STR00389## wherein R.sup.6a and R.sup.6b are each H R.sup.6c represents from 0 to 2 substituents, each such substituent being each and independently selected from the group consisting of Cl, F, Br, NO.sub.2, NH.sub.2, CN, CF.sub.3, OH, OR.sup.6d and methyl, R.sup.6d is selected from the group consisting of methyl, ethyl, propyl, and isopropyl, and s is 0, and/or wherein Xaa7 is an amino thiol residue selected from the group consisting of Cys, Cysol, AET, Hcy, cys and hcy.

15. The compound of claim 1, wherein Xaa2 is an amino acid residue selected from the group consisting of Pro, Gly, and Nmg, wherein Xaa3 is an amino acid residue selected from the group consisting of Pro and Hyp, wherein Xaa4 is the amino acid residue Thr, wherein Xaa5 is an amino acid residue selected from the group consisting of Gln and Glu, Xaa6 is an amino acid residue selected from the group consisting of Phe, 1Ni, Mpa, Otf, and Thi, and wherein Xaa7 is an amino thiol residue selected from the group consisting of Cys, Cysol, and AET.

16. The compound of claim 1, wherein the compound is a compound of formula (LI), (LII), (LIII) or (LIV): ##STR00390## ##STR00391##

17. The compound of claim 1, wherein the compound comprises a structure of formula (LI), (LII), (LIII) or (LIV): ##STR00392## ##STR00393##

18. The compound of claim 1, wherein Yc is a structure of formula (XIII): ##STR00394## preferably Yc comprises a NH group, preferably a reactive NH group, wherein the NH group allows conjugation of a moiety to Yc, preferably, the NH group is provided by the structure R.sup.c1 wherein R.sup.c1 is CH.sub.2—R.sup.c2, wherein R.sup.c2 is selected from the group consisting of a structure of any one of formulae (XXIb), (XIc) and (XIIb): ##STR00395## wherein R.sup.c4 is H or methyl and u=1, 2, 3, 4 or 5.

19. The compound of claim 1, wherein the compound comprises a Z group, wherein the Z group is covalently attached to Yc, preferably to the structure of formula (X), wherein the Z group comprises a chelator and optionally a linker, preferably the Z group is covalently attached to R.sup.c2, forming a structure of any one of formulae (XXIIc), (XId) and (XIId): ##STR00396## wherein R.sup.c4 is H or methyl and u=1, 2, 3, 4 or 5.

20. The compound of claim 1, wherein the N-terminal modification group A is the amino acid Aaa and wherein the compound comprises a Z group covalently attached to the amino acid Aaa, wherein the Z group comprises a chelator and optionally a linker, wherein, if the linker is present, the linker covalently links the chelator to the amino acid Aaa, preferably to the α-nitrogen of the amino acid Aaa, preferably the covalent linkage between the linker and the α-nitrogen of the amino acid Aaa is an amide.

21. The compound of claim 2, wherein the linker is selected from the group comprising Ttds, O2Oc, Apac, Gly, Bal, Gab, Mamb, Pamb, Ppac, 4Amc, Inp, Sni, Rni, Nmg, Cmp, PEG6, PEG12 and other PEG-amino acids, and most preferably Ttds, O2Oc, Apac, 4Amc, PEG6 and PEG12, preferably the linker amino acid is selected from the group consisting of Ttds, O2Oc and PEG6.

22. The compound of claim 1, wherein an amino acid or a peptide is attached to Xaa7, wherein the amino acid is selected from the group consisting of Asp, asp, Bal, Gly, Gab, Ser, Nmg, Bhf. and Bhk, and wherein in the peptide a majority of the amino acids of the peptide are charged or polar and the net charge of the peptide is −2, −1, 0, +1 or +2, preferably the peptide is selected from the group consisting of peptides of formula (XXXa-f)
Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16  (XXXa)
Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15  (XXXb)
Xaa10-Xaa11-Xaa12-Xaa13-Xaa14  (XXXc)
Xaa10-Xaa11-Xaa12-Xaa13  (XXXd)
Xaa10-Xaa11-Xaa12  (XXXe)
Xaa10-Xaa11  (XXXf) wherein Xaa10 is Asp, asp, Bal, Gly, Gab, Ser, Nmg, Bhf. Lys, Ttds or Bhk Xaa11 is His, his, Lys, Ttds, Arg, Ape or Ala, Xaa12 is Phe, Nmf, Tic, Aic, Ppa, Mpa, Amf, Nmf, phe, Lys, Ape, Ttds and Ppa Xaa13 is Arg, Lys, Ape, Ttds or arg, Xaa14 is Asp, Ala, asp, Lys, Ape or Ttds, Xaa15 is Ttds, Ape or Lys, and Xaa16 is Lys or Ape, wherein, optionally, Xaa11 and Xaa12 together form a single amino acid selected from the group consisting of Gab, Pamb, Cmp, Pamb, Mamb, and, optionally, Xaa10, Xaa11 and Xaa12 form together a single amino acid selected from the group consisting of Gab, Pamb, Cmp, Pamb, and Mamb, under the proviso that in the peptides of formulae (XXXa-f) Ape, if present, is the C-terminal building block.

23. The compound of claim 22, wherein the Z-group is covalently attached to the peptide, wherein the Z group comprises a chelator and optionally a linker.

24. The compound of claim 2, wherein the Z-group is covalently attached to the amino acid, wherein the Z group comprises a chelator and optionally a linker, preferably the amino acid is the amino acid attached to Xaa7 or the amino acid Aaa of the N-terminal modification group A.

25. The compound of claim 23, wherein the chelator is covalently linked to the amino acid attached to Xaa7 or the chelator is covalently linked to the C-terminal amino acid of the peptide, preferably the C-terminal amino acid of any one of peptide of formulae (LI), (LII), (LIII) and (LIV).

26. The compound of claim 2, wherein the chelator is selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, N.sub.xS.sub.4-x (N4, N2S2, N3S), Hynic, .sup.99mTc(CO).sub.3-Chelators, more preferably DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4 and most preferred DOTA, DOTAGA, NOTA, NODAGA and N4.

27. The compound of claim 26, wherein the chelator is N4Ac.

28. The compound of claim 1, wherein the compound is selected from the group consisting of compound H-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-Ttds-Lys(Bio)-NH2 (3BP-2881) of the following formula ##STR00397## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-2974) of the following formula ##STR00398## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-2975) of the following formula ##STR00399## compound H-met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-2976) of the following formula ##STR00400## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-Ttds-Lys(DOTA)-NH2 (3BP-3105) of the following formula ##STR00401## compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3168) of the following formula ##STR00402## compound DOTA-Ttds-Leu-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3172) of the following formula ##STR00403## ##STR00404## compound Ac-Met-[cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3175) of the following formula ##STR00405## compound Ac-met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3187) of the following formula ##STR00406## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Nmf-Arg-Asp-NH2 (3BP-3188) of the following formula ##STR00407## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Tic-Arg-Asp-NH2 (3BP-3189) of the following formula ##STR00408## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Aic-Arg-Asp-NH2 (3BP-3190) of the following formula ##STR00409## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Ppa-Arg-Asp-NH2 (3BP-3191) of the following formula ##STR00410## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Mpa-Arg-Asp-NH2 (3BP-3192) of the following formula ##STR00411## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Thi-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3193) of the following formula ##STR00412## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Ala-Phe-Arg-Asp-NH2 (3BP-3195) of the following formula ##STR00413## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Ala-Arg-Asp-NH2 (3BP-3196) of the following formula ##STR00414## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Ala-NH2 (3BP-3198) of the following formula ##STR00415## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-NH2 (3BP-3200) of the following formula ##STR00416## compound Ac-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3202) of the following formula ##STR00417## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Amf-Arg-Asp-NH2 (3BP-3203) of the following formula ##STR00418## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-his-Phe-Arg-Asp-NH2 (3BP-3210) of the following formula ##STR00419## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-phe-Arg-Asp-NH2 (3BP-3211) of the following formula ##STR00420## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-arg-Asp-NH2 (3BP-3212) of the following formula ##STR00421## compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-asp-NH2 (3BP-3213) of the following formula ##STR00422## compound Ac-Met-[Cys(3MeBn)-Gly-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3214) of the following formula ##STR00423## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Nmf-Arg-Ttds-Lys(DOTA)-NH2 (3BP-3275) of the following formula ##STR00424## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-phe-Arg-Ttds-Lys(DOTA)-NH2 (3BP-3276) of the following formula ##STR00425## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Ppa-arg-Ttds-Lys(DOTA)-NH2 (3BP-3277) of the following formula ##STR00426## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-NH2 (3BP-3288) of the following formula ##STR00427## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Arg-NH2 (3BP-3299) of the following formula ##STR00428## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Gab-Arg-NH2 (3BP-3300) of the following formula ##STR00429## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Pamb-Arg-NH2 (3BP-3301) of the following formula ##STR00430## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Cmp-Arg-NH2 (3BP-3302) of the following formula ##STR00431## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Pamb-Arg-NH2 (3BP-3303) of the following formula ##STR00432## compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-NH2 (3BP-3319) of the following formula ##STR00433## compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-NH2 (3BP-3320) of the following formula ##STR00434## compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Pamb-Arg-NH2 (3BP-3321) of the following formula ##STR00435## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Mamb-Arg-NH2 (3BP-3324) of the following formula ##STR00436## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-NH2 (3BP-3349) of the following formula ##STR00437## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Bal-OH (3BP-3371) of the following formula ##STR00438## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-3395) of the following formula ##STR00439## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-3396) of the following formula ##STR00440## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Bhk(DOTA)-OH (3BP-3397) of the following formula ##STR00441## compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (3BP-3398) of the following formula ##STR00442## compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3401) of the following formula ##STR00443## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ape(DOTA) (3BP-3403) of the following formula ##STR00444## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Ape(DOTA) (3BP-3404) of the following formula ##STR00445## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Otf-Cys]-NH2 (3BP-3409) of the following formula ##STR00446## compound PentylNH-urea-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3425) of the following formula ##STR00447## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3426) of the following formula ##STR00448## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3476) of the following formula ##STR00449## compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Bhk(DOTA-Ttds)-OH (3BP-3489) of the following formula ##STR00450## compound Pentyl-SO2-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3514) of the following formula ##STR00451## compound Hex-[Cys(2Lut)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3518) of the following formula ##STR00452## compound Hex-[Cys(3Lut)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3519) of the following formula ##STR00453## compound Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3555) of the following formula ##STR00454## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-1Ni-Cys]-OH (3BP-3650) of the following formula ##STR00455## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (3BP-3651) of the following formula ##STR00456## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-NH2 (3BP-3652) of the following formula ##STR00457## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Glu-Phe-Cys]-NH2 (3BP-3653) of the following formula ##STR00458## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-AET] (3BP-3654) of the following formula ##STR00459## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Gly-OH (3BP-3656) of the following formula ##STR00460## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Gab-OH (3BP-3657) of the following formula ##STR00461## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Ser-OH (3BP-3658) of the following formula ##STR00462## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Nmg-OH (3BP-3659) of the following formula ##STR00463## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Bhf-OH (3BP-3660) of the following formula ##STR00464## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Mpa-Cys]-OH (3BP-3664) of the following formula ##STR00465## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-OH (3BP-3665) of the following formula ##STR00466## compound Hex-[Cys(tMeBn(DOTA-AET))-Nmg-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3678) of the following formula ##STR00467## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Hyp-Thr-Gln-Phe-Cys]-OH (3BP-3679) of the following formula ##STR00468## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Otf-Cys]-OH (3BP-3680) of the following formula ##STR00469## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-asp-NH2 (3BP-3681) of the following formula ##STR00470## compound Pentyl-SO2-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3690) of the following formula ##STR00471## compound Pentyl-SO2-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-3691) of the following formula ##STR00472## compound Pentyl-SO2-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3692) of the following formula ##STR00473## compound Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-NH2 (3BP-3712) of the following formula ##STR00474## compound Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr-Gln-Phe-AET] (3BP-3713) of the following formula ##STR00475## compound Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Gly-OH (3BP-3714) ##STR00476## compound Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Nmg-OH (3BP-3715) of the following formula ##STR00477## compound Hex-[Cys(tMeBn(InDOTA-AET))-Nmg-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3716) of the following formula ##STR00478## compound Pentyl-SO2-[Cys(tMeBn(InDOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3717) of the following formula ##STR00479## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-NH2 (3BP-3736) of the following formula ##STR00480## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Nmg-NH2 (3BP-3737) of the following formula ##STR00481## compound Hex-[Cys(tMeBn(DOTA-AET))-Nmg-Pro-Thr-Gln-Phe-Cys]-NH2 (3BP-3744) of the following formula ##STR00482## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cysol] (3BP-3767) of the following formula ##STR00483## compound Hex-[Cys(tMeBn(InDOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3770) of the following formula ##STR00484## compound Hex-[Cys(tMeBn(DOTA-PP))-Nmg-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3771) of the following formula ##STR00485## compound Hex-[Cys-(tMeBn(H-02Oc-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3967) of the following formula ##STR00486## compound H-Ahx-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3980) of the following formula ##STR00487## compound Hex-[Cys-(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3981) of the following formula ##STR00488## compound Hex-[Cys-(tMeBn(H-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-4003) of the following formula ##STR00489## compound H-Ahx-Ttds-Nle-[Cys-(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-4004) of the following formula ##STR00490## compound Hex-[Cys-(tMeBn(N4Ac-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4063) of the following formula ##STR00491## compound Hex-[Cys-(tMeBn(N4Ac-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4088) of ##STR00492## compound Hex-[Cys-(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4089) of the following formula ##STR00493## compound Hex-[D-Cys-(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4109) of the following formula ##STR00494## compound N4Ac-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4161) of the following formula ##STR00495## compound Hex-[Cys-(tMeBn(NODAGA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4162) of the following formula ##STR00496## compound Hex-[Cys-(tMeBn(N4Ac-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4168) of the following formula ##STR00497## compound Hex-[Cys-(tMeBn(N4Ac-O2Oc-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4169) of the following formula ##STR00498## compound Hex-[Cys-(tMeBn(Bio-Ttds-Ttds-Ttds-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4170) of the following formula ##STR00499## compound Hex-[Cys-(tMeBn(H-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4181) of the following formula ##STR00500## compound Hex-[Cys(tMeBn(ATTO488-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4182) of the following formula ##STR00501## compound Hex-[Cys-(tMeBn(GaNODAGA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4184) of the following formula ##STR00502## compound Hex-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4186) of the following formula ##STR00503## compound Hex-[Cys-(tMeBn(DTPA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4214) of the following formula ##STR00504## compound N4Ac-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4219) of the following formula ##STR00505## compound N4Ac-PEG6-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4221) of the following formula ##STR00506## compound N4Ac-Glu-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4222) of the following formula ##STR00507## compound Hex-[Cys-(tMeBn(DTPA-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4224) of the following formula ##STR00508## compound N4Ac-Efa-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4243) of the following formula ##STR00509## compound N4Ac-gGlu-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4245) of the following formula ##STR00510## compound N4Ac-Glu(AGLU)-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4246) of the following formula ##STR00511## compound N4Ac-gGlu-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4247) of the following formula ##STR00512## compound N4Ac-Glu(AGLU)-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4249) of the following formula ##STR00513## compound Hex-[Cys-(tMeBn(DOTA-AET))-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4250) of the following formula ##STR00514## compound Hex-[Cys-(tMeBn(NODAGA-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4251) of the following formula ##STR00515## compound N4Ac-Glu(AGLU)-Glu(AGLU)-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4266) of the following formula ##STR00516## compound Hex-[Cys-(tMeBn(N4Ac-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4299) of the following formula ##STR00517## compound Hex-[Cys-(tMeBn(N4Ac-PEG6-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4300) of the following formula ##STR00518## compound Hex-[Cys-(tMeBn(H-SAc-Ser-Ser-Ser-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4301) of the following formula ##STR00519## compound Hex-[Cys-(tMeBn(H-Asp-Asp-Cys-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4302) of the following formula ##STR00520## compound Hex-[Cys-(tMeBn(H-Asp-Asp-Cys-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4303) of the following formula ##STR00521## compound Hex-[Cys-(tMeBn(H-SAc-Ser-Ser-Ser-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4308) of the following formula ##STR00522## compound Hex-[Cys-(tMeBn(DTPA2-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4309) of the following formula ##STR00523## compound Hex-[Cys-(tMeBn(NOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4310) of the following formula ##STR00524## compound Hex-[Cys-(tMeBn(H-HYNIC-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4342) of the following formula ##STR00525## compound Hex-[Cys-(tMeBn(NOTA-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4344) of the following formula ##STR00526## compound Hex-[Cys-(tMeBn(DTPA2-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4352) of the following formula ##STR00527## compound Hex-[Cys-(tMeBn(DTPA2-PEG6-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4353) of the following formula ##STR00528## compound Hex-[Cys-(tMeBn(DTPABzl-Glutar-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4366) of the following formula ##STR00529## compound Hex-[Cys(tMeBn(LuDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Gab-Arg-Ttds-Lys(AF488)-NH2 (3BP-4372) of the following formula ##STR00530## compound Hex-[Cys(tMeBn(LuDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Gab-Arg-Ttds-Ttds-Ttds-Lys(AF488)-NH2 (3BP-4373) of the following formula ##STR00531## compound Hex-[Cys-(tMeBn(H-HYNIC-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4376) of the following formula ##STR00532## compound Hex-[Cys-(tMeBn(PCTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4379) of the following formula ##STR00533## compound Hex-[Cys-(tMeBn(NOPO-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4380) of the following formula ##STR00534## compound Hex-[Cys-(tMeBn(HBED-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4381) of the following formula ##STR00535## compound Hex-[Cys-(tMeBn(DATA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4382) of the following formula ##STR00536## compound DOTA-Ttds-Nle-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4386) of the following formula ##STR00537## compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-4391) of the following formula ##STR00538## compound DOTA-Ttds-Nle-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-4392) of the following formula ##STR00539## and compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-4393) of the following formula ##STR00540##

29. The compound of claim 1, wherein the compound comprises a diagnostically active nuclide or a therapeutically active nuclide, wherein, preferably, the diagnostically active nuclide is a diagnostically active radionuclide, more preferably selected from the group consisting of .sup.43Sc, .sup.44Sc, .sup.51Mn, .sup.52Mn, .sup.64Cu, .sup.67Ga, .sup.68Ga, .sup.86Y, .sup.89Zr, .sup.94mTc, .sup.99mTc, .sup.111In, .sup.152Tb, .sup.155Tb, .sup.201Tl, .sup.203Pb, .sup.18F, .sup.76Br, .sup.77Br, .sup.123I, .sup.124I, .sup.125I, preferably .sup.43Sc, .sup.44Sc, .sup.64Cu, .sup.67Ga, .sup.68Ga, .sup.86Y, .sup.89Zr, .sup.99mTc, .sup.111In, .sup.152Tb, .sup.155Tb, .sup.203Pb, .sup.18F, .sup.76Br, .sup.77Br, .sup.123I, .sup.124I, .sup.125I and most preferably .sup.64Cu, .sup.68Ga, .sup.89Zr, .sup.99mTc, .sup.111In, .sup.18F, .sup.123I, and .sup.124I and wherein the therapeutically active nuclide is a therapeutically active radionuclide, more preferably selected from the group consisting of .sup.47Sc, .sup.67Cu, .sup.89Sr, .sup.90Y, .sup.153Sm, .sup.149Tb, .sup.161Tb, .sup.177Lu, .sup.188Re, .sup.188Re, .sup.212Pb, .sup.213Bi, .sup.223Ra, .sup.225Ac, .sup.226Th, .sup.227Th, .sup.131I, .sup.211At, preferably .sup.47Sc, .sup.67Cu, .sup.90Y, .sup.177Lu, .sup.188Re, .sup.212Pb, .sup.213Bi, .sup.225Ac, .sup.227Th, .sup.131I, .sup.211At and most preferably .sup.90Y, .sup.177Lu, .sup.225Ac, .sup.227Th, .sup.131I and .sup.211At.

30. The compound of claim 1, for use in a method for the diagnosis of a disease, for use in a method for the treatment of a disease, for use in a method for the identification of a subject, wherein the subject is likely to respond or likely not to respond to a treatment of a disease, wherein the method for the identification of a subject comprises carrying out a method of diagnosis using the compound, or for use in a method for the selection of a subject from a group of subjects, wherein the subject is likely to respond or likely not to respond to a treatment of a disease, wherein the method for the selection of a subject from a group of subjects comprises carrying out a method of diagnosis using the compound for use in a method for the stratification of a group of subjects into subjects which are likely to respond to a treatment of a disease, and into subjects which are not likely to respond to a treatment of a disease, wherein the method for the stratification of a group of subjects comprises carrying out a method of diagnosis using the compound.

31. A composition, preferably a pharmaceutical composition, wherein the composition comprises a compound according to claim 1 and a pharmaceutically acceptable excipient.

32. A kit comprising a compound according to claim 1, one or more optional excipient(s) and optionally one or more device(s), whereby the device(s) is/are selected from the group comprising a labeling device, a purification device, a handling device, a radioprotection device, an analytical device or an administration device.

Description

[0594] The present invention is now further illustrated by reference to the following figures and examples from which further features, embodiments and advantages, may be taken, wherein

[0595] FIG. 1 shows a radiochromatogram of .sup.177Lu-3BP-3407 in formulation buffer containing 100 mg/mL ascorbate and 5 mg/mL L-methionine analyzed immediately after synthesis;

[0596] FIG. 2 shows a radiochromatogram of .sup.177Lu-3BP-3407 in formulation buffer containing 100 mg/mL ascorbate and 5 mg/mL L-methionine analyzed six days after synthesis;

[0597] FIG. 3 shows a radiochromatogram of .sup.177Lu-3BP-3554 in formulation buffer containing 100 mg/mL ascorbate and 5 mg/mL L-methionine analyzed immediately after synthesis;

[0598] FIG. 4 shows a radiochromatogram of .sup.177Lu-3BP-3554 in formulation buffer containing 100 mg/mL ascorbate and 5 mg/mL L-methionine analyzed six days after synthesis;

[0599] FIG. 5 shows the percentage of injected dose per gram of tissue (% ID/g) uptake in the kidney, liver, bloodpool and HEK-FAP tumor as determined by SPECT-imaging of .sup.111In-3BP-3105 (A) and .sup.111In-3BP-3168 (B) 1 h, 3 h, 6 h and 24 h post injection into the mouse model;

[0600] FIG. 6 shows the percentage of injected dose per gram of tissue (% ID/g) uptake in the kidney, liver, bloodpool and HEK-FAP tumor as determined by SPECT-imaging of .sup.111In-3BP-3320 (A) and .sup.111In-3BP-3321 (B) 1 h, 3 h, 6 h and 24 h post injection into the mouse model;

[0601] FIG. 7 shows the percentage of injected dose per gram of tissue (% ID/g) uptake in the kidney, liver, bloodpool and HEK-FAP tumor as determined by SPECT-imaging of .sup.111In-3BP-3275 (A) and .sup.111In-3BP-3397 (B) 1 h, 3 h, 6 h and 24 h post injection into the mouse model;

[0602] FIG. 8 shows the percentage of injected dose per gram of tissue (% ID/g) uptake in the kidney, liver, bloodpool and HEK-FAP tumor as determined by SPECT-imaging of .sup.111In-3BP-3398 (A) and .sup.111In-3BP-3407 (B) 1 h, 3 h, 6 h and 24 h post injection into the mouse model;

[0603] FIG. 9 shows the percentage of injected dose per gram of tissue (% ID/g) uptake in the kidney, liver, bloodpool and HEK-FAP tumor as determined by SPECT-imaging of .sup.111In-3BP-3554 (A) and .sup.111In-3BP-3652 (B) 1 h, 3 h, 6 h and 24 h post injection into the mouse model;

[0604] FIG. 10 shows the percentage of injected dose per gram of tissue (% ID/g) uptake in the kidney, liver, bloodpool and HEK-FAP tumor as determined by SPECT-imaging of .sup.111In-3BP-3654 (A) and .sup.111In-3BP-3656 (B) 1 h, 3 h, 6 h and 24 h post injection into the mouse model;

[0605] FIG. 11 shows the percentage of injected dose per gram of tissue (% ID/g) uptake in the kidney, liver, bloodpool and HEK-FAP tumor as determined by SPECT-imaging of .sup.111In-3BP-3659 (A) and .sup.111In-3BP-3678 (B) 1 h, 3 h, 6 h and 24 h post injection into the mouse model;

[0606] FIG. 12 shows the percentage of injected dose per gram of tissue (% ID/g) uptake in the kidney, liver, bloodpool and HEK-FAP tumor as determined by SPECT-imaging of .sup.111In-3BP-3692 (A) and .sup.111In-3BP-3767 (B) 1 h, 3 h, 6 h and 24 h post injection into the mouse model;

[0607] FIG. 13 shows SPECT-images of .sup.111In-3BP-3554 1 h, 3 h, 6 h, 24 h and 48 h post injection into mice with HEK-FAP tumors

[0608] FIG. 14 shows SPECT-images of .sup.111In-3BP-3767 1 h, 3 h, 6 h, 24 h and 48 h post injection into mice with HEK-FAP tumors;

[0609] FIG. 15 A shows tumor growth over time in mice with HEKFAP tumors treated with vehicle, cold compound .sup.natLu-3BP-3554, 30 MBq (low dose) .sup.177Lu-3BP-3554, and 60 MBq(high dose) .sup.177Lu-3BP-3554;

[0610] FIG. 15 B shows percent body weight changes over time in mice with HEK-FAP tumors treated with vehicle, cold compound .sup.natLu-3BP-3554, 30 MBq (low dose) .sup.177Lu-3BP-3554, and 60 MBq (high dose) .sup.177Lu-3BP-3554;

[0611] FIG. 16 A shows representative SPECT/CT images over time of the biodistribution 60 MBq .sup.177Lu-3BP-3554 in mice with HEK-FAP tumors;

[0612] FIG. 16 B shows representative SPECT/CT images over time of the biodistribution 30 MBq .sup.177Lu-3BP-3554 in mice with HEK-FAP tumors;

[0613] FIG. 17 A shows representative SPECT/CT images of four different sarcoma PDX models 3 h after .sup.111In-3BP-3554 administration;

[0614] FIG. 17 B shows % ID/g uptake of .sup.111In-3BP-3554 in four different sarcoma PDX models, 3 hours post injection;

[0615] FIG. 18 A shows tumor growth over time in mice with Sarc4809 PDX tumors treated with vehicle, cold compound .sup.natLu-3BP-3554, 30 MBq .sup.177Lu-3BP-3554 or 60 MBq .sup.177Lu-3BP-3554;

[0616] FIG. 18 B shows body weight changes over time in mice with sarcoma Sarc4809 PDX tumors treated with vehicle, cold compound .sup.natLu-3BP-3554, 30 MBq .sup.177Lu-3BP-3554, or 60 MBq .sup.177Lu-3BP-3554; and

[0617] FIG. 19 shows the amino acid sequences of human fibroblast activating protein (FAP) (SEQ ID NO: 1), human dipeptidyl peptidase 4(DDP4) (SEQ ID NO: 2) and human prolyl endopeptidase (PREP) (SEQ ID NO: 3).

[0618] The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The synthetic descriptions and specific examples that follow are only intended for the purposes of illustration, and are not to be construed as limiting in any manner to make compounds of the disclosure by other methods.

EXAMPLES

[0619] Abbreviations used in the instant application and the following examples in particular are as follows: [0620] 4PL means four parameter logistic curve fitting [0621] A means Angström [0622] ACN means acetonitrile [0623] Ahx means 6-Aminohexanoic acid [0624] AMC means 7-amino-4-methylcoumarin [0625] amu means atomic mass unit [0626] aq. means aqueous [0627] AUC.sub.inf means area under the curve extrapolated to infinity [0628] BSA means bovine serum albumin [0629] C.sub.0 means initial concentration of the compound [0630] CAF means cancer associated fibroblasts [0631] CL means clearance [0632] CM means ChemMatrix™ [0633] CT means computed tomography [0634] Cy5 means Cyanine-5 [0635] DAD means Diode Array Detector [0636] DCM means dichloromethane [0637] Dde means N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) [0638] DEG means di ethylene glycol dimethacrylate [0639] DIC means N,N′-Diisopropylcarbodiimide [0640] DICOM means Digital Imaging and Communications in Medicine [0641] DIPEA means diisopropylethylamine [0642] DMF means N,N-dimethylformamide [0643] DMSO means dimethyl sulfoxide [0644] DOTA means 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [0645] DOTA(tBu).sub.3-OH means Tri-tert-butyl-1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetate [0646] DPP means dipeptidyl peptidase [0647] EC means electron capture [0648] EC.sub.50 means half-maximal excitatory concentration [0649] ECACC means European Collection of Authenticated Cell Cultures [0650] EDC means 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0651] EMEM means Eagle's Minimum Essential Medium [0652] eq or eq. means equivalent [0653] ESI means electrospray ionization [0654] Et.sub.2O means Diethylether [0655] EtOAc means ethylacetate [0656] FACS means fluorescence-activated cell sorting [0657] FAP means fibroblast activation protein [0658] Fb means background fluorescent intensity [0659] FBS means fetal bovine serum [0660] FGF21 means fibroblast growth factor 21 [0661] FITC means 5(6)-fluorescein isothiocyanate [0662] Fmoc means 9-Fluorenylmethoxycarbonyl [0663] FRET means Fluorescence Resonance Energy Transfer [0664] Ft means fluorescent intensity [0665] Gab means gamma-amino butyric acid [0666] GABA means gamma-amino butyric acid [0667] h means hour(s) [0668] HATU means O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate [0669] HBST means SPR running buffer [0670] HEK-FAP means human embryonic kidney 293 cells expressing human FAP [0671] HEPES means 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [0672] HFIP means hexafluoro-2-isopanol [0673] HOAc means acetic acid [0674] HOAt means 1-Hydroxy-7-azabenzotriazole [0675] HPLC means high performance liquid chromatography [0676] HPLC/MS means high performance liquid chromatography/mass spectrometry [0677] IC.sub.50 means half-maximal inhibitory concentration [0678] ID/g means injected dose per gram [0679] IS means isomeric transition [0680] iTLC-SG means instant thin layer chromatography-silica-gel [0681] K2EDTA means ethylenediaminetetraacetic acid dipotassium [0682] K.sub.D means dissociation constant [0683] kDa means 1000 Dalton [0684] K.sub.i means inhibitory constant [0685] k.sub.off means dissociation rate [0686] k.sub.on means association rate [0687] LC/TOF-MS means Liquid chromatography/time-of-flight/mass spectrometry [0688] LC-MS means high performance liquid chromatography coupled with mass spectrometry [0689] LDH means lactate dehydrogenase [0690] Leu means leucine [0691] LiOH means lithium hydroxide [0692] M means molar or mol per Liter [0693] m/z means mass divided by charge [0694] max. means maximum [0695] MeOH means Methanol [0696] MeV means mega electron volt [0697] min means minute(s) [0698] MMP means matrix metalloproteinase [0699] MRM means multiple reaction monitoring [0700] MTBE means Methyl-tert-butylether [0701] Mit means Methyltrityl [0702] MTV means mean tumor volume [0703] MW means molecular weight [0704] n.d. means not determined [0705] Na.sub.2SO.sub.4 means sodium sulfate [0706] NaCl means sodium chloride [0707] NaHCO.sub.3 means sodium hydrogencarbonate [0708] NCA means non-compartmental analysis [0709] NHS means N-Hydroxysuccinimide [0710] NMP means 1-methyl-2-pyrrolidone [0711] NOS means not otherwise specified [0712] Oic means L-octahydroindol-2-carbonsaure [0713] p.a. means: for analytical purpose (quality grade) [0714] p.i. means post injection [0715] Pbf means 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl [0716] PBS means phosphate buffered saline [0717] PDX means patient-derived xenograft [0718] PET means positron emission tomography [0719] pIC50 means the negative log of the IC50 value when converted to molar [0720] POP means prolyl oligopeptidase [0721] ppm means parts per million [0722] PREP means prolyl endopeptidase [0723] prep. means preparative [0724] PS means polystyrene [0725] Q-TOF means quadrupole time of flight [0726] Ref means reference [0727] RFU means relative fluorescence unit [0728] RLB means radioligand binding assay [0729] RMCE means recombinase-mediated cassette exchange [0730] RP means reversed phase [0731] R.sub.t means retention time [0732] RT means room temperature [0733] RU means resonance units [0734] SAR means structure activity relationship [0735] sat. means saturated [0736] SCID means severe combined immunodeficiency [0737] SCK means single cycle kinetics [0738] sec or s means second [0739] SF means spontaneous fission [0740] SPECT means single photon emission computed tomography [0741] SPPS means Solid Phase Peptide Synthesis [0742] t.sub.1/2 means terminal half-life [0743] tBu means tert. butyl [0744] TFA means trifluoroacetate or trifluoroacetic acid [0745] TG means TentaGel [0746] TGI means tumor growth inhibition [0747] THF means Tetrahydrofuran [0748] TIPS means triisopropylsilane [0749] TLC means thin layer chromatography [0750] TME means tumor microenvironment [0751] t.sub.R means retention time [0752] UHPLC means ultrahigh performance liquid chromatography [0753] UV means ultraviolet [0754] V.sub.ss means volume of distribution at steady state [0755] V.sub.z means volume of distribution in the terminal phase

Example 1: Material and Methods

[0756] The materials and methods as well as general methods are further illustrated by the following examples.

Solvents:

[0757] Solvents were used in the specified quality without further purification. Acetonitrile (Super Gradient, HPLC, VWR—for analytical purposes; PrepSolv, Merck—for preparative purposes); dichloromethane (synthesis, Roth); ethyl acetate (synthesis grade, Roth); N,N-dimethylformamide (peptide synthesis grade, Biosolve); 1-methyl-2-pyrolidone (peptide grade, IRIS BioTech) 1,4-dioxane (reinst, Roth); methanol (p. a., Merck).

[0758] Water: Milli-Q Plus, Millipore, demineralized.

Chemicals:

[0759] Chemicals were synthesized according to or in analogy to literature procedures or purchased from Sigma-Aldrich-Merck (Deisenhofen, Germany), Bachem (Bubendorf, Switzerland), VWR (Darmstadt, Germany), Novabiochem (Merck Group, Darmstadt, Germany), Acros Organics (distribution company Fisher Scientific GmbH, Schwerte, Germany), Iris Biotech (Marktredwitz, Germany), Amatek Chemical (Jiangsu, China), Roth (Karlsruhe, Deutschland), Molecular Devices (Chicago, USA), Biochrom (Berlin, Germany), Peptech (Cambridge, Mass., USA), Synthetech (Albany, Oreg., USA), Pharmacore (High Point, N.C., USA), PCAS Biomatrix Inc (Saint-Jean-sur-Richelieu, Quebec, Canada), Alfa Aesar (Karlsruhe, Germany), Tianjin Nankai Hecheng S&T Co., Ltd (Tianjin, China), CheMatech (Dijon, France) and Anaspec (San Jose, Calif., USA) or other companies and used in the assigned quality without further purification.

[0760] Boc.sub.4N4Ac—OH was synthesized according to a literature procedure (Maecke et al. Chem. Eur. J., 2010, 16, 7, 2115).

##STR00365##

Cells:

[0761] HT29 (ECACC Cat. No. 91072201) and WI-38 (ECACC Cat. No. 90020107) were purchased from ECACC and HEK293 cells expressing human FAP (Q12884) were produced by InSCREENeX GmbH (Braunschweig, Germany) using recombinase-mediated cassette exchange (RMCE). The RMCE procedure is described by Nehlsen et al. (Nehlsen, et al., BMC Biotechnol, 2009, 9: 100).

HPLC/MS Analyses

[0762] HPLC/MS analyses were performed by injection of 5 μl of a solution of the sample, using a 2 step gradient for all chromatograms (5-65% B in 12 min, followed by 65-90% in 0.5 min, A: 0.1% TFA in water and B: 0.1% TFA in ACN). RP columns were from Agilent (Type Poroshell 120, 2.7 μm, EC-C18, 50×3.00 mm, flow 0.8 ml, HPLC at room temperature); Mass spectrometer Agilent 6230 LC/TOF-MS, ESI ionization. MassHunter Qualitative Analysis B.07.00 SP2 was used as software. UV detection was done at λ=230 nm. Retention times (R.sub.t) are indicated in the decimal system (e.g. 1.9 min=1 min 54 s) and are referring to detection in the UV spectrometer. For the evaluation of observed compound masses the ‘Find Compounds by Formula’-feature was used. In particular, the individual ‘neutral mass of a compound (in units of Daltons)’-values and the corresponding isotope distribution pattern were used to confirm compound identity. The accuracy of the mass spectrometer was approx. ±5 ppm.

Preparative HPLC:

[0763] Preparative HPLC separations were done with reversed phase columns (Kinetex 5μ XB-C18 100 Å, 150×30 mm from Phenomenex or RLRP-S 8μ, 100 Å, 150×25 mm) as stationary phase. As mobile phase 0.1% TFA in water (A) and 0.1% TFA in ACN (B) were used which were mixed in linear binary gradients. The gradients are described as: “10 to 40% B in 30 min”, which means a linear gradient from 10% B (and correspondingly 90% A) to 40% B (and correspondingly 60% A) was run within 30 min. Flow-rates were within the range of 30 to 50 ml/min. A typical gradient for the purification of the compounds of the invention started at 5-25% B and ended after 30 min at 35-50% B and the difference between the percentage B at end and start was at least 10%. A commonly used gradient was “15 to 40% B in 30 min”.

General Procedures for Automated/Semi-Automated Solid-Phase Synthesis:

[0764] Automated solid-phase of peptides and polyamides was performed on a Tetras Peptide Synthesizer (Advanced ChemTech) in 50 μmol and 100 μmol scales. Manual steps were performed in plastic syringes equipped with frits (material PE, Roland Vetter Laborbedarf OHG, Ammerbuch, Germany). The amount of reagents in the protocols described corresponds to the 100 μmol scale, unless stated otherwise.

[0765] Solid-phase synthesis was performed on polystyrene (cross linked with 1,4-divinylbenzene (PS) or di (ethylene glycol) dimethacrylate (DEG)), ChemMatrix (CM) or TentaGel (TG) resin. Resin linkers were trityl, wang and rink amide.

Resin Loading:

[0766] In case of the trityl linker the attachment of the first building block (resin loading) was performed as follows. The resin (polystyrene (PS) trityl chloride, initial loading: 1.8 mmol/g) was swollen in DCM (5 ml) for 30 minutes and subsequently washed with DCM (3 ml, 1 minute). Then the resin was treated with a mixture of the corresponding building block (0.5 mmol, 5 eq.) and DIPEA (350 μl, 3.5 mmol, 35 eq.) in DCM (4 ml) for 1 hour. Afterwards the resin was washed with methanol (5 ml, 5 minutes) and DMF (3 ml, 2×1 minute).

[0767] In case of the Wang linker pre-loaded resins (polystyrene (PS) and TentaGel (TG)) were employed.

[0768] In case of the rink amide linker the attachment of the first residue the resin (CM, DEG) was performed with the same procedure as for the chain assembly as described below.

Alloc/Allyl-Deprotection:

[0769] After swelling in DMF, the resin was washed with DMF and DCM. DCM was de-oxygenated by passing a stream of nitrogen through the stirred solvent. The oxygen-free solvent was used to wash the resin trice. Then 2 ml of a 2 M solution of barbituric acid in oxygen-free DCM and 1 ml of a 25 μM solution of Tetrakis(triphenylphosphine)palladium(0) in oxygen-free DCM were added to the resin. The resin was agitated for 1 hour and then washed with DCM, MeOH, DMF, 5% DIPEA in DMF, 5% dithiocarbamate in DMF, DMF and DCM (each washing step was repeated 3 times with 3 ml, 1 minute).

Fmoc-Deprotection:

[0770] After swelling in DMF, the resin was washed with DMF and then treated with piperidine/DMF (1:4, 3 ml, 2 and 20 minutes) and subsequently washed with DMF (3 ml, 5×1 minute).

Dde-Deprotection:

[0771] After swelling in DMF, the resin was washed with DMF and then treated with hydrazine-hydrate/DMF (2/98, 3 ml 2×10 minutes) and subsequently washed with DMF (3 ml, 5×1 minute).

Mtt-Deprotection:

[0772] After swelling in DCM, the resin was washed with DCM and then treated with HFIP/DCM (7/3, 4-6 ml, 4 hours) and subsequently washed with DCM (3 ml, 3×1 minute), DMF (3 ml, 3×1 ml) and DIPEA (0.9 M in DMF, 3 ml, 1 minute).

Solutions of Reagents:

[0773] Building Blocks (0.3 M in DMF or NMP), DIPEA (0.9 M in DMF), HATU (0.4 M in DMF), Acetic anhydride (0.75 M in DMF)

Coupling: Coupling of Building Blocks/Amino Acids (Chain Assembly):

[0774] Unless otherwise stated, coupling of building blocks was performed as follows: After subsequent addition of solutions of the corresponding building block (1.7 ml, 5 eq.), DIPEA solution (1.15 ml, 10 eq.) and HATU solution (1.25 ml, 5 eq.) the resin was shaken for 45 min.

[0775] If necessary, the resin was washed with DMF (3 ml, 1 minute) and the coupling step was repeated.

Terminal Acetylation:

[0776] After addition of DIPEA solution (1.75 ml, 16 eq.) and acetic anhydride solution (1.75 ml, 13 eq.) the resin was shaken for 10 minutes. Afterwards the resin was washed with DMF (3 ml, 6×1 minutes).

Cleavage Method A: Cleavage of Protected Fragments from Hyper-Acid Labile Resin:

[0777] After the completion of the assembly of the sequence the resin was finally washed with DCM (3 ml, 4×1 minute) and then dried in the vacuum. Then the resin was treated with HFIP/DCM (7/1, 4 ml, 4 hours) and the collected solution evaporated to dryness. The residue was purified with preparative HPLC or used without further purification.

Cleavage Method B: Cleavage of Unprotected Fragments (Complete Resin Cleavage):

[0778] After the completion of the assembly of the sequence the resin was finally washed with DCM (3 ml, 4×1 minute), dried in the vacuum overnight and treated with TFA, EDT, water and TIPS (94/2.5/2.5/1) for 2 h (unless otherwise stated). Afterwards the cleavage solution was poured into a chilled mixture of MTBE and cyclohexane (1/1, 10-fold excess compared to the volume of cleavage solution), centrifuged at 4° C. for 5 minutes and the precipitate collected and dried in the vacuum. The residue was lyophilized from water/acetonitrile prior to purification or further modification.

Cleavage Method C: Cleavage of Protective Groups of Peptides in Solution

[0779] The protected/partially protected compound was dissolved in TFA, water and TIPS (95/2.5/2.5) for 2 h (unless otherwise stated). Afterwards the cleavage solution was poured into a chilled mixture of MTBE and cyclohexane (1/1, 10-fold excess compared to the volume of cleavage solution), centrifuged at 4° C. for 5 minutes and the precipitate collected and dried in the vacuum. The residue was lyophilized from water/acetonitrile prior to purification or further modification.

[0780] More relevant Fmoc-solid-phase-peptide synthesis methods are described in detail in “Fmoc Solid Phase Peptide Synthesis” Editors W. Chan, P. White, Oxford University Press, USA, 2000. Compounds were named using MestreNova version 12 Mnova IUPAC Name plugin (Mestrelab Research, S.L.), or AutoNom version 2.2 (Beilstein Informationssysteme Copyright© 1988-1998, Beilstein Institut fir Literatur der Organischen Chemie licensed to Beilstein Chemiedaten and Software GmbH, where appropriate.

Preparation of Compounds:

[0781] Specific embodiments for the preparation of compounds of the invention are provided in the following examples. Unless otherwise specified, all starting materials and reagents are of standard commercial grade, and are used without further purification, or are readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize in light of the instant disclosure that starting materials and reaction conditions may be varied including additional steps employed to produce compounds encompassed by the present invention.

[0782] One general synthesis route for compounds of the invention comprises [0783] 1. Solid Phase Peptide Synthesis (SPPS) of a linear peptide precursor with two thiol moieties. [0784] 2. the thiol-site specific cyclization of this linear peptide precursor with [0785] a. a bis(bromomethyl)benzene derivative or [0786] b. a tris(bromomethyl)benzene derivative. [0787] 3. In case of cyclizations with a tris(bromomethyl)benzene derivative the intermediate formed in the cyclization reaction was further reacted with a linker that enabled the attachment of a chelator.

Example 2: Synthesis of Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Nmf-Arg-Asp-NH2 (3BP-3188)

[0788] The sequence (Ac-Met-Cys-Pro-Pro-Thr-Glu-Phe-Cys-Asp-His-Nmf-Arg-Asp-NH2) of the peptide was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 50 μmol scale on a Rink amide resin. After performing the steps of ‘Cleavage method B’ the lyophilized crude peptide residue was dissolved in 60 ml of a 1:1 mixture of ammonium bicarbonate solution (50 mM, pH=8.5) and acetonitrile. To this mixture a solution of 14.5 mg α,α′-dibromo-m-xylene (55 μmol, 1.1 eq compared to initial resin loading) in 0.5 ml acetonitrile was added. Upon completion of the cyclization reaction 50 μl TFA were added and the solvent removed by lyophilization. The remainder was subjected to HPLC purification (15 to 45% B in 30 min—Kinetex) to yield 8.61 mg of the pure title compound (9.8%). HPLC: R.sub.t=5.87 min. LC/TOF-MS: exact mass 1753.716 (calculated 1753.705). C.sub.79H.sub.107N.sub.19O.sub.21S.sub.3(MW=1755.011).

Example 3: Synthesis of DOTA-Ttds-Leu-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3172)

[0789] The sequence (DOTA-Ttds-Leu-Cys-Pro-Pro-Thr-Glu-Phe-Cys-Asp-His-Phe-Arg-Asp-NH2) of the peptide was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 50 μmol scale on a Rink amide resin. After performing the steps of ‘Cleavage method B’ the lyophilized crude peptide residue was dissolved in 60 ml of a 1:1 mixture of ammonium bicarbonate solution (50 mM, pH=8.5) and acetonitrile. To this mixture a solution of 14.5 mg α,α′-dibromo-m-xylene (55 μmol, 1.1 eq compared to initial resin loading) in 0.5 ml acetonitrile was added. Upon completion of the cyclization reaction 50 μl TFA were added and the solvent removed by lyophilization. The remainder was subjected to HPLC purification (20 to 45% B in 30 min—Kinetex) to yield 35.46 mg of the pure title compound (29.8%). HPLC: Rt=5.9 min. LC/TOF-MS: exact mass 2368.091 (calculated 2368.087). C.sub.107H.sub.157N.sub.25O.sub.32S.sub.2(MW=2369.676).

Example 4: Synthesis of Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Ppa-arg-Ttds-Lys(DOTA)-NH2(3BP-3277)

[0790] The sequence (Hex-Cys-Pro-Pro-Thr-Glu-Phe-Cys-Asp-His-Ppa-arg-Ttds-Lys(Mtt)-NH.sub.2) of the peptide was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 50 μmol scale on a Rink amide resin. Then a ‘Mtt deprotection’ described in the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ was performed to liberate the ε-amino function of the C-terminal lysine residue of the peptide resin. DOTA(tBu).sub.3-OH (143.3 mg, 250 μmol, 5 eq compared to the initial resin loading) was dissolved in 0.6 ml of a 0.4 M solution of HATU in DMF and 0.65 ml of a 0.9 M of DIPEA in DMF. After leaving the mixture for 1 minute for pre-activation it was added to the resin. An hour later 0.2 ml of a 3.2 M of DIC in DMF was added and the gentle agitation of the resin continued for a further hour. The resin was thoroughly washed and subjected to the ‘Cleavage method B’ protocol. The lyophilized remainder (linear, branched peptide Hex-Cys-Pro-Pro-Thr-Glu-Phe-Cys-Asp-His-Ppa-arg-Ttds-Lys(DOTA)-NH2) was dissolved in 60 ml of a 1:1 mixture of ammonium bicarbonate solution (50 mM, pH=8.5) and acetonitrile. To this mixture a solution of 14.5 mg α,α′-dibromo-m-xylene (55 μmol, 1.1 eq compared to initial resin loading) in 0.5 ml acetonitrile was added. Upon completion of the cyclization reaction 50 μl TFA were added and the solvent removed by lyophilization. The remainder was subjected to HPLC purification (15 to 40% B in 30 min—Kinetex) to yield 17.18 mg of the pure title compound (14.5%). HPLC: R.sub.t=5.8 min. LC/TOF-MS: exact mass 2367.150 (calculated 2367.139). C.sub.108H.sub.162N.sub.26O.sub.30S.sub.2 (MW=2368.735).

Example 5: Synthesis of N4Ac-Glu(AGLU)-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4246)

[0791] The sequence (N4Ac-Glu(OAll)-Ttds-Nle-Cys-Pro-Pro-Thr-Gln-Phe-Cys-OH) of the peptide was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 50 μmol scale on a Fmoc-Cys(Trt) WANG Tentagel resin. An ‘Alloc/Allyl-deprotection’ was performed to effect the removal of the Allyl ester protecting group. 3,4;5,6-di-O-isopropylidene-1-amino-1-deoxy-D-glucitol (J. Org. Chem., 2002, 75, 3685) (52.2 mg, 200 μmol, 4 eq.), Oxyma (28.4 mg, 200 μmol, 4 eq.) and DIC (31 μL, 200 μmol, 4 eq.) were dissolved in DMF (1.5 mL), the solution added to resin and the latter agitated for 90 minutes. The resin was washed and the coupling of the amino-glucitol building block repeated one more time. The resin was washed, dried and finally treated with TFA, water, TIPS and 1,3-Dimethoxybenzol (90/2.5/2.5/5, 3 mL) for 2 hours to effect detachment from the resin and removal of the side chain protecting groups. After precipitation and lyophilization from water/acetonitrile the crude linear peptide was dissolved in 60 ml of a 1:1 mixture of ammonium bicarbonate solution (50 mM, pH=8.5) and acetonitrile. To this mixture a solution of 14.5 mg α,α′-dibromo-m-xylene (55 μmol, 1.1 eq compared to initial resin loading) in 0.5 ml acetonitrile was added. Upon completion of the cyclization reaction 50 μl TFA were added and the solvent removed by lyophilization. The remainder was subjected to HPLC purification (15 to 40% B in 30 min—Kinetex) to yield 8.97 mg of the pure title compound (10%). HPLC: R.sub.t=5.5 min. LC/TOF-MS: exact mass 1789.901 (calculated 1789.899). C.sub.81H.sub.131N.sub.17O.sub.24S.sub.2 (MW=1791.142).

Example 6: Synthesis of Pentyl-SO2-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2(3BP-3692)

[0792] The sequence (H-Cys-Pro-Pro-Thr-Gln-Phe-Cys-Asp-NH2) of the peptide was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 50 μmol scale on a Rink amide resin. The N-terminal sulfonamide was attached by treatment of the resin bound peptide with a solution of n-pentyl sulfonyl chloride (42.7 μl, 300 μmol, 6 eq) and 2,4,6-collidine (29.7 μl, 225 μmol, 4.5 eq). After overnight agitation the resin was thoroughly washed and subjected to the ‘Cleavage method B’ protocol. The lyophilized remainder (linear peptide Pentyl-SO2-Cys-Pro-Pro-Thr-Gln-Phe-Cys-Asp-NH2) was dissolved in 60 ml of a 1:1 mixture of ammonium bicarbonate solution (50 mM, pH=8.5) and acetonitrile. To this mixture a solution of 26.8 mg 1,3,5-tris(bromomethyl)benzene (75 μmol, 1.5 eq compared to initial resin loading) in 0.5 ml acetonitrile was added. After stirring the solution for 1 hour 43 mg piperazine (500 μmol, 10 eq compared to initial resin loading) were added. After 2 hours 50 μl TFA were added and the solvent removed by lyophilization. The remainder was subjected to HPLC purification (15 to 45% B in 30 min—Kinetex) to yield 9.15 mg (7.4 μmol) of the peptide intermediate Pentyl-SO2-[Cys(tMeBn(H-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (14.7%). To the solution of the latter in 150 μl DMSO 2.5 μl DIPEA were added to adjust the pH value to approximately 7.5-8. Then 8.4 mg of DOTA-NHS (11 μmol, 1.5 eq compared to the peptide intermediate) in 100 μl DMSO were added. During the course of the LC/TOF-MS monitored reaction 2.5 μl DIPEA was added 3 times to re-adjust the pH value to the starting value. After reaction completion the solution was subjected to HPLC purification (15 to 45% B in 30 min—Kinetex) to yield 7.09 mg of the pure title compound (8.7% overall yield). HPLC: R.sub.t=6.0 min. LC/TOF-MS: exact mass 1628.706 (calculated 1628.704). C.sub.72H.sub.108N.sub.16O.sub.21S.sub.3 (MW=1629.924).

Example 7: Synthesis of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4089)

[0793] Example 7a: Synthesis of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4089) by Two Different Methods

[0794] The synthesis of the title compound was either performed by initially synthesizing the linear peptide precursor on solid phase with a subsequent solution phase cyclization (either in non-aqueous solution (Method A) or in aqueous solution (Method B) or by performing all steps on solid phase. The latter approach (Example 7b) served as starting point for further derivatization.

[0795] For the first approach (Example 7a) Fmoc-Cys(Trt)-OH was loaded onto the trityl resin as described in the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 50 μmol scale. Onto this resin the sequence (Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-OH) of the peptide was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’. After performing the steps of ‘Cleavage method B’ the crude peptide was lyophilized and cyclized in solution by two alternative methods.

[0796] Cyclization Method A:

[0797] The crude peptide (based on 50 μmol resin loading) was dissolved in 10 ml of a 1:1 mixture of ethanol and acetonitrile. To this mixture first 35 μl DIPEA and then 23.7 mg of 1,3,5-tris(bromomethyl)benzene (66.6 μmol, 1.3 eq compared to initial resin loading) were added. The solution was stirred for 1 hour and then 42.8 mg cysteamine (555 μmol, 11 eq compared to initial resin loading) was added. After 1 hour the solvents was removed in vacuo and 25 ml of a 1:1 mixture of acetonitrile and water (containing 50 μl TFA were added). The solvents were removed by lyophilization. The remainder was subjected to HPLC purification (15 to 45% B in 30 min—Kinetex) to yield 17.8 mg (16.4 μmol) of the intermediate Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (32.8%).

[0798] Cyclization Method B:

[0799] The crude peptide (based on 50 μmol resin loading) was dissolved in 60 ml of a 1:1 mixture of ammonium bicarbonate solution (50 mM, pH=8.5) and acetonitrile. To this mixture a solution of 26.8 mg 1,3,5-tris(bromomethyl)benzene (75 μmol, 1.5 eq compared to initial resin loading) in 0.5 ml acetonitrile was added. The solution was stirred for 1 hour and then 38.6 mg cysteamine (500 μmol, 10 eq compared to initial resin loading) was added. After 2 hours 50 μl TFA were added and the solvent removed by lyophilization. The remainder was subjected to HPLC purification (15 to 45% B in 30 min—Kinetex) to yield 19.47 mg (18 μmol) of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (35.9%).

[0800] Both solution-based cyclization methods perform similar and achieve comparable yields and similar purities.

Example 7b: Synthesis of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel (3BP-4089 Bound on Peptide Resin)

[0801] For the synthesis of the resin bound title compound a Fmoc-Cys(Trt)-WANG Tentagel resin was used as starting material. Onto the latter the sequence (Hex-Cys(Trt)-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys-OH) of the peptide was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 1 mmol scale. After completion of the sequence assembly the resin was washed with DCM (3×1 min) Then the trityl protecting groups were selectively removed from the resin be treatment with a solution of TFA, TIPS and DCM (5/5/90, 5×5 min). The resin was washed with DCM, DMF, 0.9 M DIPEA in DMF, DMF, DCM (3/3/2/3/3) and dried in the vacuum. The following cyclization was performed in 200 μmol portions. To this end the resin was swollen in DMF and then treated with a solution of 1,3,5-Tris(bromomethyl)benzene (86 mg, 240 μmol, 1.2 eq), DIPEA (235 μL, 1 mmol, 5 eq) in 2 mL DMF at 50° C. for 90 minutes. The solution was removed, the resin washed with DMF and then a solution of cysteamine (154.3 mg, 2 mmol, 10 eq) added to the resin. The resin was agitated for another 90 minutes at 50° C. After washing the resin with DMF and DCM (3/3) the peptide resin (Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel) was dried and kept for further derivatization. By this procedure it may happen that the Trityl-group at Glutamine is either partially or fully deprotected. In any case this does not interfere with the optional derivatization of the free amino group of AET.

Example 8: Synthesis of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3554)

[0802] To the solution of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (19.5 mg, 18 μmol, 3BP-4089—described in Example 7a) in 300 μl DMSO, 5 μl DIPEA were added to adjust the pH value to approximately 7.5-8. Then 20.5 mg of DOTA-NHS (27 μmol, 1.5 eq compared to the peptide intermediate) in 200 μl DMSO were added. During the course of the LC/TOF-MS monitored reaction 5 μl DIPEA was added 3 times to re-adjust the pH value to the starting value. After reaction completion the solution was subjected to HPLC purification (15 to 45% B in 30 min—Kinetex) to yield 20.44 mg of the pure title compound (77.4% yield). HPLC: R.sub.t=5.9 min. LC/TOF-MS: exact mass 1469.640 (calculated 1469.639). C.sub.67H.sub.99N.sub.13O.sub.18S.sub.3 (MW=1470.780).

Example 9: Synthesis of Hex-[Cys-(tMeBn(NODAGA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4162)

[0803] (R)-NODA-GA(tBu).sub.3-OH (50 mg, 92 μmol, 1 eq), HATU (35 mg, 92 μmol, 1 eq) and DIPEA (32 μL, 184 μmol, 2 eq) were dissolved in 0.4 mL DMF. The mixture was stirred for 2 min to ensure pre-activation of the chelator building block. Then this mixture was added to the solution of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (100 mg, 92 μmol, 3BP-4089—described in Example 7a) in 2 mL DMF and 20 μL DIPEA which was added to adjust the pH value of the peptide solution to approximately 7.5-8. After 90 min all volatiles were removed in the vacuum and the remainder subjected to lyophilization. After performing the steps of ‘Cleavage method C’ the crude peptide was lyophilized and subsequently subjected to HPLC purification (15 to 45% B in 30 min—Kinetex) to yield 48.54 mg of the pure title compound (33.7% yield). HPLC: Rt=6.8 min. LC/TOF-MS: exact mass 1440.613 (calculated 1440.613). C.sub.66H.sub.96N.sub.12O.sub.18S.sub.3 (MW=1441.739).

Example 10: Synthesis of Hex-[Cys-(tMeBn(DTPA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4214)

[0804] DTPA(tBu).sub.4-OH (Diethylenetriamine-N,N,N″,N″-tetra-tert-butyl acetate-N′-acetic acid) (28.5 mg, 46 μmol, 1 eq), HATU (17.5 mg, 46 μmol, 1 eq) and DIPEA (16 μL, 92 μmol, 2 eq) were dissolved in 100 μL DMF. The mixture was stirred for 2 min to ensure pre-activation of the chelator building block. Then this mixture was added to the solution of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (50 mg, 46 μmol, 3BP-4089—described in Example 7a) in 600 μL DMF and 10 μL DIPEA which was added to adjust the pH value of the peptide solution to approximately 7.5-8. After 180 min all volatiles were removed in the vacuum and the remainder subjected to lyophilization. After performing the steps of ‘Cleavage method C’ the crude peptide was lyophilized and subsequently subjected to HPLC purification (15 to 45% B in 30 min—Kinetex) to yield 15.4 mg of the pure title compound (22.9% yield). HPLC: R.sub.t=6.5 min. LC/TOF-MS: exact mass 1458.587 (calculated 1458.587). C.sub.65H.sub.94N.sub.12O.sub.20S.sub.3 (MW=1459.711).

Example 11: Synthesis of Hex-[Cys-(tMeBn(N4Ac-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4088)

[0805] Fmoc-O2Oc-OH was loaded onto the trityl resin as described in the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 100 μmol scale. Onto this resin the sequence Boc.sub.4N4Ac—OH was coupled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’. After performing the steps of ‘Cleavage method A’ the crude protected conjugated was lyophilized (crude yield 154 mg) and used without purification in the next step. Boc.sub.4N4Ac-O2Oc-OH (75 mg, 100 μmol, 1.2 eq), HATU (38 mg, 100 μmol, 1.2 eq) and DIPEA (68 μL, 400 μmol, 4 eq) were dissolved in 500 μL DMF. The mixture was stirred for 2 min to ensure pre-activation of the chelator-linker building block. Then this mixture was added to the solution of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (90 mg, 83 μmol, 3BP-4089—described in Example 7a) in 2 mL DMF and 20 μL DIPEA which was added to adjust the pH value of the peptide solution to approximately 7.5-8. After 60 min all volatiles were removed in the vacuum and the remainder subjected to lyophilization. After performing the steps of ‘Cleavage method C’ the crude peptide was lyophilized and subsequently subjected to HPLC purification (20 to 45% B in 30 min—Kinetex) to yield 67.4 mg of the pure title compound (55% yield). HPLC: R.sub.t=6.0 min. LC/TOF-MS: exact mass 1414.681 (calculated 1414.681). C.sub.65H.sub.102N.sub.14O.sub.15S.sub.3 (MW=1415.791).

Example 12: Synthesis of Hex-[Cys-(tMeBn(ReON4Ac-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4147)

[0806] To the solution of Hex-[Cys-(tMeBn(N4Ac-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (25 mg, 17.7 μmol, 1 eq) and Trichlorooxobis(triphenylphosphine)-rhenium(V) (14.7 mg, 17.7 μmol, 1 eq) in ethanol (3 mL) 10 μL DIPEA were added. The mixture was stirred overnight at 50° C. After reduction of the reaction solvent volume to approx. 0.5 mL an equal amount of water was added and the resulting solution subjected to HPLC purification (15 to 45% B in 30 min, eluents without TFA modifier—Kinetex) to yield 6.1 mg of the pure title compound (21% yield). HPLC: R.sub.t=6.0 min. LC/TOF-MS: exact mass 1612.606 (calculated 1612.608). C.sub.65H.sub.98N.sub.14O.sub.16ReS.sub.3 (MW=1613.%8).

Example 13: Synthesis of Hex-[Cys-(tMeBn(Bio-Ttds-Ttds-Ttds-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4170)

[0807] Fmoc-Ttds-OH was loaded onto the trityl resin as described in the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 100 μmol scale. Onto this resin the sequence (Bio-Ttds-Ttds-Ttds-Ttds-OH) was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’. After performing the steps of ‘Cleavage method B’ the remainder was lyophilized and subjected to HPLC purification to yield 116.8 mg (80%) of the purified intermediate product. Bio-Ttds-Ttds-Ttds-Ttds-OH (86 mg, 59 μmol, 1 eq), HATU (22.4 mg, 59 μmol, 1 eq) and DIPEA (20.5 μL, 120 μmol, 2 eq) were dissolved in 1 mL DMF. The mixture was stirred for 2 min to ensure pre-activation of the biotin-linker conjugate building block. Then this mixture was added to the solution of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (64 mg, 59 μmol, 3BP-4089—described in Example 7a) in 2 mL DMF and 20 μL DIPEA which was added to adjust the pH value of the peptide solution to approximately 7.5-8. After 120 min all volatiles were removed in the vacuum and the remainder subjected to lyophilization. The remainder was subjected to HPLC purification (20 to 45% B in 30 min—Kinetex) to yield 27.46 mg of the pure title compound (18% yield). HPLC: R.sub.t=7.3 min. LC/TOF-MS: exact mass 2518.274 (calculated 2518.273). C.sub.117H.sub.191N.sub.19O.sub.33S.sub.4(MW=2520.145).

Example 14: Synthesis of Hex-[Cys-(tMeBn(DTPA-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4224)

[0808] Boc-O2Oc-OH (dicyclohexylamine salt) (20.5 mg, 46 μmol, 1 eq), Oxyma (9.8 mg, 69 μmol, 1.5 eq) and DIC (10.7 μL, 69 μmol) were dissolved in DMF and stirred for 5 min to ensure pre-activation of the linker building block. Then this mixture was added to the solution of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (50 mg, 46 μmol, 3BP-4089—described in Example 7a) in 2 mL DMF and 20 μL DIPEA which was added to adjust the pH value of the peptide solution to approximately 7.5-8. After 4 hours another portion of Boc-O2Oc-OH (equal amounts as stated above) was pre-activated and added to the peptide reaction solution. The mixture was left to stir overnight. Then all volatiles were removed in vacuum and the remainder lyophilized from water/acetonitrile. The freeze-dried crude product was subject to ‘Cleavage method C’ to remove the Boc-protecting group and subsequently purified by preparative HPLC (15 to 45% B in 30 min—Kinetex) to yield 16.25 mg of the pure intermediate peptide Hex-[Cys(tMeBn(H-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (29% yield). For the next step DTPA(tBu).sub.4-OH (Diethylenetriamine-N,N,N″,N″-tetra-tert-butyl acetate-N′-acetic acid) (8.2 mg, 13.2 μmol, 1 eq), HATU (5 mg, 13.2 μmol, 1 eq) and DIPEA (4.6 μL, 26.4 μmol, 2 eq) were dissolved in 100 μL DMF. After stirring for 2 min to ensure pre-activation of the chelator building block this mixture was added to the solution of the 16.25 mg intermediate peptide (13.2 μmol) whose pH value had been adjusted to approximately 7.5-8 by addition of 5 μL DIPEA. After 180 minutes all volatiles were removed in the vacuum and the remainder subjected to HPLC purification (35 to 75% B in 30 min—Kinetex) to yield 12.76 mg (7 μmol) of the pure protected intermediate peptide Hex-[Cys(tMeBn(DTPA(tBu).sub.4-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (53% yield). The latter was subject to ‘Cleavage method C’, all volatiles removed in the vacuum and the remainder subjected to HPLC purification (15 to 45% B in 30 min—Kinetex) to yield 5.9 mg (3.7 μmol) of the pure title compound (53% yield−overall yield: 8%). HPLC: R.sub.t=6.6 min. LC/TOF-MS: exact mass 1603.661 (calculated 1603.661). C.sub.71H.sub.105N.sub.13O.sub.23S.sub.3 (MW=1604.868).

Example 15: Synthesis of Hex-[Cys-(tMeBn(H-HYNIC-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4342)

[0809] Boc-HYNIC-OH (9.2 mg, 36 μmol, 1.3 eq), HATU (13.7 mg, 36 μmol, 1.3 eq) and DIPEA (12.2 μL, 72 μmol, 2.6 eq) were dissolved in 250 μL DMF. The mixture was stirred for 2 min to ensure pre-activation of the chelator-linker building block. Then this mixture was added to the solution of Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (30 mg, 27.8 μmol, 1 eq, 3BP-4089—described in Example 7a) in 400 μL DMF and 10 μL DIPEA which was added to adjust the pH value of the peptide solution to approximately 7.5-8. After 60 min all volatiles were removed in the vacuum, the remainder redissolved in DMSO and this solution directed to HPLC purification (25 to 55% B in 30 min—Kinetex) to yield 17.8 mg (13.5 μmol, 48.5%) of the intermediate protected peptide. The removal of the Boc-protecting group was achieved by treatment of the peptide with HCl (37%, 40 μL). The resulting mixture was dissolved with sodium acetate buffer (pH 4.5, 1.8 mL) and acetonitrile (0.2 mL) and the solution subjected to HPLC purification (20 to 50% B (0.02% formic acid in place of 0.1% TFA) in 30 min—Kinetex) to yield 1.15 mg (0.9 μmol) of the pure title compound (7% yield−overall yield: 3.4%). HPLC: R.sub.t=6.9 min. LC/TOF-MS: exact mass 1218.505 (calculated 1218.502). C57H78N12O12S3 (MW=1219.503).

Example 16: Synthesis of Hex-[Cys-(tMeBn(NOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4310)

[0810] The starting point for the synthesis of the title compounds was the 3BP-4089 peptide resin from example 7b (Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel) which was used in a 100 μmol scale. According to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ NOTA(tBu).sub.2-OH (2-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazonan-1-yl)acetic acid) was coupled. After drying the resin was subjected to ‘Cleavage method B’. The crude peptide was lyophilized and subsequently purified by preparative HPLC (20 to 45% B in 30 min—Kinetex) to yield 5.6 mg (4.1 μmol) of the pure title compound (4%). HPLC: R.sub.t=6.8 min. LC/TOF-MS: exact mass 1368.592 (calculated 1368.592). C.sub.63H.sub.92N.sub.12O.sub.16S.sub.3(MW=1369.676).

Example 17: Synthesis of Hex-[Cys-(tMeBn(DTPA2-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4309)

[0811] The starting point for the synthesis of the title compounds was the 3BP-4089 peptide resin from example 7b (Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel) which was used in a 100 μmol scale. According to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ DTPA2(tBu).sub.4-OH (3,6,9-tris(2-(tert-butoxy)-2-oxoethyl)-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid) was coupled. After drying the resin was subjected to ‘Cleavage method B’. The crude peptide was lyophilized and subsequently purified by preparative HPLC (20 to 45% B in 30 min—Kinetex) to yield 5.8 mg (3.9 μmol) of the pure title compound (3.9%). HPLC: R.sub.t=6.5 min. LC/TOF-MS: exact mass 1458.587 (calculated 1458.587). C65H94N12O20S3 (MW=1459.711).

Example 18: Synthesis of Hex-[Cys-(tMeBn(NODAGA-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4251)

[0812] The starting point for the synthesis of the title compounds was the 3BP-4089 peptide resin from example 7b (Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel) which was used in a 50 μmol scale. According to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ consecutively Fmoc-O2Oc-OH and (R)-NODA-GA(tBu).sub.3-OH were coupled. After drying the resin was subjected to ‘Cleavage method B’. The crude peptide was lyophilized and subsequently purified by preparative HPLC (15 to 45% B in 30 min—Kinetex) to yield 4.31 mg (2.7 μmol) of the pure title compound (5.4%). HPLC: R.sub.t=6.7 min. LC/TOF-MS: exact mass 1585.687 (calculated 1585.687). C.sub.72H.sub.107N.sub.13O.sub.21S.sub.3(MW=1586.8%).

Example 19: Synthesis of Hex-[Cys-(tMeBn(NOTA-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4344)

[0813] The starting point for the synthesis of the title compounds was the 3BP-4089 peptide resin from example 7b (Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel) which was used in a 100 μmol scale. According to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ consecutively Fmoc-Ttds-OH and NOTA(tBu).sub.2-OH (2-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazonan-1-yl)acetic acid) were coupled. After drying the resin was subjected to ‘Cleavage method B’. The crude peptide was lyophilized and subsequently purified by preparative HPLC (20 to 45% B in 30 min—Kinetex) to yield 10.1 mg (6.0 μmol) of the pure title compound (6%). HPLC: R.sub.t=6.8 min. LC/TOF-MS: exact mass 1670.776 (calculated 1670.776). C.sub.77H.sub.118N.sub.14O.sub.21S.sub.3 (MW=1672.043).

Example 20: Synthesis of Hex-[Cys-(tMeBn(DTPA2-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4352)

[0814] The starting point for the synthesis of the title compounds was the 3BP-4089 peptide resin (Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel) from example 7b which was used in a 100 μmol scale. According to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ Fmoc-Ttds-OH and DTPA2(tBu).sub.4-OH (3,6,9-tris(2-(tert-butoxy)-2-oxoethyl)-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid) were coupled. After drying the resin was subjected to ‘Cleavage method B’. The crude peptide was lyophilized and subsequently purified by preparative HPLC (20 to 45% B in 30 min—Kinetex) to yield 6.87 mg (3.9 μmol) of the pure title compound (3.9%). HPLC: R.sub.t=6.7 min. LC/TOF-MS: exact mass 1760.771 (calculated 1760.771). C.sub.79H.sub.120N.sub.14O.sub.25S.sub.3 (MW=1762.078).

Example 21: Synthesis of Hex-[Cys-(tMeBn(H-SAc-Ser-Ser-Ser-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4301)

[0815] The starting point for the synthesis of the title compounds was the 3BP-4089 peptide resin from example 7b (Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel) which was used in a 100 μmol scale. According to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ Fmoc-Ser(tBu)-OH was coupled 3 times, followed by the coupling of Tritylmercapto acetic acid. After drying the resin was subjected to ‘Cleavage method B’. The crude peptide was lyophilized and subsequently purified by preparative HPLC (20 to 45% B in 30 min—Kinetex) to yield 5.25 mg (3.7 μmol) of the pure title compound (3.7%).

[0816] HPLC: R.sub.t=6.8 min. LC/TOF-MS: exact mass 1418.553 (calculated 1418.538). C.sub.62H.sub.90N.sub.12O.sub.18S.sub.4 (MW=1419.714).

Example 22: Synthesis of Hex-[Cys-(tMeBn(H-Asp-Asp-Cys-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4302)

[0817] The starting point for the synthesis of the title compounds was the 3BP-4089 peptide resin (Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel) from example 7b which was used in a 100 μmol scale. According to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ Fmoc-Ttds-OH, Fmoc-Cys(Trt)-OH, and twice Fmoc-Asp(OtBu)-OH were coupled. After drying the resin was subjected to ‘Cleavage method B’. The crude peptide was lyophilized and subsequently purified by preparative HPLC (20 to 45% B in 30 min—Kinetex) to yield 5.52 mg (3.2 μmol) of the pure title compound (3.2%). HPLC: R.sub.t=6.8 min. LC/TOF-MS: exact mass 1718.705 (calculated 1718.706). C.sub.76H.sub.114N.sub.14O.sub.23S.sub.4 (MW=1720.066).

Example 23: Synthesis of Hex-[Cys-(tMeBn(DTPABzl-Glutar-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4366)

[0818] The starting point for the synthesis of the title compounds was the 3BP-4089 peptide resin from example 7b (Hex-[Cys(tMeBn(H-AET))-Pro-Pro-Thr(tBu)-Gln(Trt)-Phe-Cys]-O-WANG-Tentagel) which was used in a 100 μmol scale. Glutaric anhydride (57 mg, 0.5 mmol, 5 eq.) and DIPEA (165 μL, 1 mmol, 10 eq.) were dissolved in DMF (3 mL), the solution added to resin and the latter agitated for 1 hour. p-NH.sub.2-Bn-DTPA(OtBu)5 (S-2-(4-Aminobenzyl)-diethylenetriamine penta-tert-butyl acetate, 155 mg, 200 μmol, 2 eq.), Oxyma (27.2 mg, 200 μmol, 2 eq.), DIPEA (70 μL, 400 μmol, 4 eq.) and DIC (31 μL, 200 μmol, .sup.2 eq.) were dissolved in DMF (1.7 mL), the solution added to the resin and the latter agitated for 90 minutes at 50° C. The addition of DIC was repeated and the agitation of the resin at 50° C. repeated for another 90 minutes. Thereafter another portion of DIC was added and the resin agitated at room temperature overnight. The next the DIC addition with subsequent agitation at 50° C. was repeated another 3 times. Then the resin was washed and subjected to ‘Cleavage method B’. The crude peptide was lyophilized and subsequently purified by preparative HPLC (20 to 40% B in 30 min—Kinetex) to yield 10.53 mg (6.3 μmol) of the pure title compound (6.3%). HPLC: R.sub.t=7.0 min. LC/TOF-MS: exact mass 1677.688 (calculated 1677.676). C.sub.77H.sub.107N.sub.13O.sub.2S.sub.3 (MW=1678.948).

Example 24: Synthesis of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-AET](3BP-3654)

[0819] This synthesis was performed as the synthesis of 3BP-3554 described in Example 7a except for the fact that a commercially available pre-loaded aminoethanthiol trityl resin was used for the assembly of the linear peptide precursor Hex-Cys-Pro-Pro-Thr-Gln-Phe-AET. After performing all the steps described in Example 7 HPLC purification (15 to 45% B in 30 min—Kinetex) finally yielded 21.25 mg of the pure title compound (29.8% overall yield). HPLC: R.sub.t=6.2 min. LC/TOF-MS: exact mass 1425.661 (calculated 1425.649). C.sub.66H.sub.99N.sub.13O.sub.16S.sub.3 (MW=1426.771).

Example 25: Synthesis of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cysol](3BP-3762)

[0820] This synthesis was performed as the synthesis of 3BP-3554 described in Example 7a except for the fact that Fmoc-Cysteinol(Trt)-OH was loaded onto the trityl resin. Differing from the description in the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ this was achieved as follows: 50 μmol of trityl resin were swollen in THF and subsequently washed with dry THF (3 times). Then the resin was treated with a solution of Fmoc-Cysteinol(Trt)-OH (57 mg, 100 μmol, 2 eq) and pyridine (16.1 μl, 200 μmol, 4 eq) in dry THF (1 ml) for 20 hours at 60° C. After washing the resin thoroughly (THF, MeOH, DCM, DMF, 3 ml, 3×1 min) the linear peptide precursor Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cysol was assembled as described in the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’. After performing all the steps described in Example 7 HPLC purification (15 to 45% B in 30 min—Kinetex) finally yielded 7.8 mg of the pure title compound (10.7% overall yield). HPLC: R.sub.t=5.9 min. LC/TOF-MS: exact mass 1455.666 (calculated 1455.660). C.sub.67H.sub.101N.sub.13O.sub.17S.sub.3 (MW=1456.797).

Example 26: Synthesis of Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2(3BP-3407)

[0821] a) Synthesis of Intermediate Hex-[Cys(tMeBn(H-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH.sub.2 by Two Different Cyclization Methods

[0822] The sequence (Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-Asp-NH2) of the peptide was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 50 μmol scale on a Rink amide resin. After performing the steps of ‘Cleavage method B’ the crude peptide was lyophilized and cyclized by two alternative methods.

[0823] Cyclization Method A:

[0824] The crude peptide (based on 50 μmol resin loading) was dissolved in 10 ml of a 1:1 mixture of ethanol and acetonitrile. To this mixture first 30 μl DIPEA and then 26.8 mg of 1,3,5-tris(bromomethyl)benzene (75 μmol, 1.5 eq compared to initial resin loading) were added. After stirring the solution for 45 minutes a solution of 43 mg piperazine (500 μmol, 10 eq compared to initial resin loading) in 200 μl of a 1:1 mixture of ethanol/acetonitrile was added. After 1 hour the solvents were removed in vacuo, 25 ml of a 1:1 mixture of acetonitrile and water (containing 50 μl TFA) was added and the solvents were removed by lyophilization. The remainder was subjected to HPLC purification (15 to 40% B in 30 min—Kinetex) to yield 15.3 mg (12.7 μmol) of the peptide intermediate Hex-Cys(tMeBn(H-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (25.3%).

[0825] Cyclization Method B:

[0826] The crude peptide (based on 50 μmol resin loading) was dissolved in 60 ml of a 1:1 mixture of ammonium bicarbonate solution (50 mM, pH=8.5) and acetonitrile. To this mixture 26.8 mg of 1,3,5-tris(bromomethyl)benzene (75 μmol, 1.5 eq compared to initial resin loading) were added. The solution was stirred for 1 hour and 43 mg piperazine (500 μmol, 10 eq compared to initial resin loading) were added. After 6 hours 100 μl TFA were added and the solvent removed by lyophilization. The remainder was subjected to HPLC purification (15 to 40% B in 30 min—Kinetex) to yield 17.2 mg (14.2 μmol) of the peptide intermediate Hex-Cys(tMeBn(H-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (28.4%).

[0827] Both cyclization methods perform similar and achieve comparable yields and similar purities.

[0828] b) Final Steps of Synthesis of Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH.sub.2(3BP-3407): DOTA-Coupling and Purification

[0829] To the solution of the intermediate (obtained by cyclization method B) in 200 μl DMSO 2.5 μl DIPEA were added to adjust the pH value to approximately 7.5-8. Then 16.3 mg of DOTA-NHS (21.4 μmol, 1.5 eq compared to the peptide intermediate) in 100 μl DMSO were added. During the course of the LC/TOF-MS monitored reaction 2.5 μl DIPEA was added 5 times to re-adjust the pH value to the starting value. After reaction completion the solution was subjected to HPLC purification (15 to 40% B in 30 min—Kinetex) to yield 19.1 mg (12.0 μmol) of the pure title compound (85%). HPLC: R.sub.t=5.70 min. LC/TOF-MS: exact mass 1592.737 (calculated 1592.737). C.sub.73H.sub.108N.sub.16O.sub.20S.sub.2 (MW=1593.866).

Example 27: Synthesis of Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH.SUB.2 .(3BP-3476)

[0830] The sequence (Hex-Cys-Pro-Pro-Thr-Gln-Phe-Cys-Asp-NH2) of the peptide was assembled according to the ‘General procedures for Automated/Semi-automated Solid-Phase Synthesis’ in a 50 μmol scale on a Rink amide resin. After performing the steps of ‘Cleavage method B’ the crude peptide was lyophilized and cyclized by two alternative methods.

[0831] Cyclization Method A:

[0832] The crude peptide (based on 50 μmol resin loading) was dissolved in 10 ml of a 1:1 mixture of ethanol and acetonitrile. To this mixture first 25 μl DIPEA and then a solution of 15.9 mg 1,3,5-tris(bromomethyl)benzene (60 μmol, 1.2 eq compared to initial resin loading) in 60 μl acetonitrile/ethanol 1:1 was added. The solution was stirred for 90 minutes and then 77 mg dithiothreitol (500 μmol, 10 eq compared to initial resin loading) was added. After stirring overnight the solvents were removed in vacuo and 30 ml of a 1:1 mixture of acetonitrile and water (containing 50 μl TFA) were added. The solvents were removed by lyophilization. The remainder was subjected to HPLC purification (15 to 40% B in 30 min—Kinetex) to yield 16.0 mg (14.4 μmol) of the pure title compound (28.8%). HPLC: R.sub.t=7.36 min. LC/TOF-MS: exact mass 1108.476 (calculated 1108.472). C.sub.52H.sub.72N.sub.10O.sub.13S.sub.2(MW=1109.320).

[0833] Cyclization Method B:

[0834] The lyophilized crude peptide (based on 50 μmol resin loading) was dissolved in 60 ml of a 1:1 mixture of ammonium bicarbonate solution (50 mM, pH=8.5) and acetonitrile. To this mixture a solution of 15.8 mg α,α′-dibromo-m-xylene (60 μmol, 1.2 eq compared to initial resin loading) in 0.5 ml acetonitrile was added. Upon completion of the cyclization reaction 50 μl TFA were added and the solvent removed by lyophilization. The remainder was subjected to HPLC purification (25 to 45% B in 30 min—Kinetex) to yield 16.9 mg (15.2 μmol) of the pure title compound (30.4%). HPLC: R.sub.t=7.24 min. LC/TOF-MS: exact mass 1108.476 (calculated 1108.472). C.sub.52H.sub.72N.sub.10O.sub.13S.sub.2 (MW=1109.320).

[0835] Both cyclization methods (A and B) are similar effective in terms of yields and purity and are therefore both applicable.

Example 28: Preparation of DOTA-Transition Metal Complexes of Compounds of the Invention

[0836] A. General Procedure for the Preparation of a Peptide Comprising DOTA-Transition Metal-Complexes from Corresponding Peptides Comprising Uncomplexed DOTA

[0837] A 0.1 mM solution of the peptide comprised by uncomplexed DOTA in [0838] 0.4 M sodium acetate, pH=5 (Buffer A) (in case of Cu(II), Zn(II), In(III), Lu(III) or Ga(III) complexes) or [0839] 0.1 M ammonium acetate, pH=8 (Buffer B) (in case of Eu(III) complexes)
was diluted with a solution 0.1 mM solution of the corresponding metal salt in water whereby the molar ratio of peptide to metal was adjusted to 1:3. The solution was stirred [0840] at 50° C. for 20 minutes (also referred to herein as Condition A) (in case of In(III), Lu(III), Ga(II), Zn(II) or Cu(II) complexes) or [0841] at room temperature overnight (also referred to herein as Condition B)(in case of Eu(II) complexes).

[0842] The solution was then applied to [0843] HPLC purification (also referred to herein as Purification A) or [0844] solid phase extraction (also referred to herein as Purification B). [0845] In case of solid phase extraction 250 mg Varian Bondesil-ENV was placed in a 15 ml polystyrene syringe, pre-washed with methanol (1×5 ml) and water (2×5 ml). Then the reaction solution was applied to the column. Thereafter elution was performed with water (2×5 ml—to remove excess salt), 5 ml of 50% ACN in water as first fraction and each of the next fractions were eluted with 5 ml of 50% ACN in water containing 0.1% TFA.

[0846] In either case (HPLC purification or solid phase extraction) fractions containing the pure product were pooled and freeze dried.

B. Indium-Complex of Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH.SUB.2 .(3BP-3590)

[0847] The complex was prepared starting from 25 mg peptide 3BP-3407 (15.7 μmol) dissolved in Buffer A, diluted with a solution of InCl.sub.3×4 H.sub.2O which was treated with Condition A. In the purification step ‘Purification A’ was employed (15 to 40% B in 30 min—RLRP-S) to yield 18.24 mg of the pure title compound (68.1% yield). HPLC: R.sub.t=5.6 min. LC/TOF-MS: exact mass 1702.622 (calculated 1702.617). C.sub.73H.sub.105InN.sub.16O.sub.20S.sub.2 (MW=1705.663).

C. Gallium-Complex of Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH.SUB.2 .(3BP-3592)

[0848] The complex was prepared starting from 25 mg peptide 3BP-3407 (15.7 μmol) dissolved in Buffer A, diluted with a solution of Ga(NO.sub.3).sub.3×H.sub.2O which was treated with Condition A. In the purification step ‘Purification A’ was employed (15 to 40% B in 30 min—RLRP-S) to yield 16.78 mg of the pure title compound (69.3% yield). HPLC:R.sub.t=5.7 min. LC/TOF-MS: exact mass 1658.664 (calculated 1658.639). C.sub.73H.sub.105GaN.sub.16O.sub.20S.sub.2 (MW=1660.568).

D. Lutetium-Complex of Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH.SUB.2.(3BP-3591)

[0849] The complex was prepared starting from 25 mg peptide 3BP-3407 (15.7 μmol) dissolved in Buffer A, diluted with a solution of LuCl.sub.3 which was treated with Condition A. In the purification step ‘Purification A’ was employed (15 to 40% B in 30 min—RLRP-S) to yield 16.66 mg of the pure title compound (60.1% yield). HPLC: R.sub.t=5.6 min. LC/TOF-MS: exact mass 1764.654 (calculated 1764.654). C.sub.73H.sub.105LuN.sub.16O.sub.20S.sub.2 (MW=1765.812).

E. Europium-Complex of Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH.SUB.2 .(3BP-3661)

[0850] The complex was prepared starting from 9.5 mg peptide (6 μmol) 3BP-3407 dissolved in Buffer B, diluted with a solution of EuCl.sub.3×6 H.sub.2O which was treated with Condition B. In the purification step ‘Purification B’ was employed to yield 8.24 mg of the pure title compound (79.3% yield). HPLC: R.sub.t=5.7 min. LC/TOF-MS: exact mass 1740.636 (calculated 1740.633). C.sub.73H.sub.105EuN.sub.16O.sub.20S.sub.2 (MW=1742.809).

F. Indium-Complex of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3623)

[0851] The complex was prepared starting from 6 mg peptide 3BP-3554 (4.1 μmol) dissolved in Buffer A, diluted with a solution of InCl.sub.3×4 H.sub.2O which was treated with Condition A. In the purification step ‘Purification B’ was employed to yield 5.26 mg of the pure title compound (81% yield). HPLC: R.sub.t=5.8 min. LC/TOF-MS: exact mass 1579.524 (calculated 1579.520). C.sub.67H.sub.96InN.sub.13O.sub.18S.sub.3 (MW=1582.574).

G. Lutetium-Complex of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3624)

[0852] The complex was prepared starting from 6 mg peptide 3BP-3554 (4.1 μmol) dissolved in Buffer A, diluted with a solution of LuCl.sub.3 which was treated with Condition A. In the purification step ‘Purification B’ was employed to yield 5.5 mg of the pure title compound (82% yield). HPLC: R.sub.t=5.9 min. LC/TOF-MS: exact mass 1641.560 (calculated 1641.557). C.sub.67H.sub.96LuN.sub.13O.sub.18S.sub.3 (MW=1642.723).

H. Gallium-Complex of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3949)

[0853] The complex was prepared starting from 7.9 mg peptide 3BP-3554 (5.4 μmol) dissolved in Buffer A, diluted with a solution of Ga(NO.sub.3).sub.3×H.sub.2O which was treated with Condition A. In the purification step ‘Purification B’ was employed to yield 4.2 mg of the pure title compound (51% yield). HPLC: R.sub.t=6.6 min. LC/TOF-MS: exact mass 1535.543 (calculated 1535.541). C.sub.67H.sub.96GaN.sub.13O.sub.18S.sub.3 (MW=1537.479).

I. Europium-Complex of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3662)

[0854] The complex was prepared starting from 3.4 mg peptide 3BP-3554 (2.3 μmol) dissolved in Buffer B, diluted with a solution of EuCl.sub.3×6 H.sub.2O which was treated with Condition B. In the purification step ‘Purification B’ was employed to yield 3.1 mg of the pure title compound (83% yield). HPLC: R.sub.t=5.9 min. LC/TOF-MS: exact mass 1617.541 (calculated 1617.536). C.sub.67H.sub.96EuN.sub.13O.sub.18S.sub.3 (MW=1619.721).

J. Copper(II)-Complex of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4293)

[0855] The complex was prepared starting from 18 mg peptide 3BP-3554 (12.2 μmol) dissolved in Buffer A, diluted with a solution of Cu(OAc).sub.2 which was treated with Condition A. In the purification step ‘Purification B’ was employed to yield 16.5 mg of the pure title compound (88% yield). HPLC: R.sub.t=6.5 min. LC/TOF-MS: exact mass 1530.553 (calculated 1530.553). C.sub.67H.sub.97CuN.sub.13O.sub.18S.sub.3 (MW=1532.310).

K. Zink-Complex of Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4343)

[0856] The complex was prepared starting from 20 mg peptide 3BP-3554 (13.6 μmol) dissolved in Buffer A, diluted with a solution of ZnCl.sub.2 which was treated with Condition A. In the purification step ‘Purification B’ was employed to yield 16.1 mg of the pure title compound (77% yield). HPLC: R.sub.t=6.4 min. LC/TOF-MS: exact mass 1531.553 (calculated 1531.553). C.sub.67H.sub.97N.sub.13O.sub.18S.sub.3Zn (MW=1534.160).

L. Gallium-Complex of Hex-[Cys(tMeBn(NODAGA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4184)

[0857] The complex was prepared starting from 7.4 mg peptide 3BP-4162 (5.1 μmol) dissolved in Buffer A, diluted with a solution of Ga(NO.sub.3).sub.3×H.sub.2O which was treated with Condition A. In the purification step ‘Purification B’ was employed to yield 6.3 mg of the pure title compound (80% yield). HPLC: R.sub.t=6.5 min. LC/TOF-MS: exact mass 1506.515 (calculated 1506.515). C.sub.66H.sub.93GaN.sub.12O.sub.18S.sub.3 (MW=1508.438).

Example 29: Plasma Stability Assay

[0858] In order to determine the stability of selected compounds of the invention in human and mouse plasma, a plasma stability assay was carried out. Such plasma stability assay measures degradation of compounds of the present invention in blood plasma. This is an important characteristic of a compound as compounds, with the exception of pro-drugs, which rapidly degrade in plasma, generally show poor in vivo efficacy. The results show that those compounds are highly stable in human and mouse plasma. The stability is sufficient for the diagnostic, therapeutic and theragnostic use of these compounds according to the present invention.

[0859] The plasma stability samples were prepared by spiking 50 μl plasma aliquots (all K2EDTA) with 1 μl of a 0.5 mM compound stock solution in DMSO. After vortexing the samples were incubated in a Thermomixer at 37° C. for 0, 4 and 24 hours. After incubation the samples were stored on ice until further treatment. All samples were prepared in duplicates.

[0860] A suitable internal standard was added to each sample (1 μl of a 0.5 mM stock solution in DMSO). Protein precipitation was performed using two different methods depending on the compound conditions as indicated in Table 8.

A) 250 μl of acetonitrile containing 1% trifluoroacetic acid was added. After incubation at room temperature for 30 min the precipitate was separated by centrifugation and 150 μl of the supernatant was diluted with 150 μl of 1% aqueous formic acid.
B) 150 μl of a zinc sulphate precipitation agent containing 78% 0.1 M zinc sulphate and 22% acetonitrile was added. After incubation at room temperature for 30 min the precipitate was separated by centrifugation. To 100 μl of the supernatant 10 μl of 1% formic acid was added followed by further incubation at 60° C. for 10 min to complete the formation of the zinc chelate, if the compound contains a free DOTA moiety.

[0861] The determination of the analyte in the clean sample solutions was performed on an Agilent 1290 UHPLC system coupled to an Agilent 6530 Q-TOF mass spectrometer. The chromatographic separation was carried out on a Phenomenex BioZen XB-C18 HPLC column (50×2 mm, 1.7 μm particle size) with gradient elution using a mixture of 0.1% formic acid in water as eluent A and acetonitrile as eluent B (2% B to 41% in 7 min, 800 μl/min, 40° C.). Mass spectrometric detection was performed in positive ion ESI mode by scanning the mass range from m/z 50 to 3000 with a sampling rate of 2/sec.

[0862] From the mass spectrometric raw data the ion currents for the double or triple charged monoisotopic signal was extracted for both, the compound and the internal standard.

[0863] Quantitation was performed by external matrix calibration with internal standard using the integrated analyte signals.

[0864] Additionally, recovery was determined by spiking a pure plasma sample that only contained the internal standard after treatment with a certain amount of the compound.

[0865] Carry-over was evaluated by analysis of a blank sample (20% acetonitrile) after the highest calibration sample.

[0866] The results of this assay performed on some of the compounds according to the present invention are given in the following Table 8. The result is stated as “% intact compound remaining after 4 h or 24 h” and means that from the amount of material at the start of the experiment the stated percentage is detected as unchanged material at the end of the experiment by LC-MS quantification. Since all compounds are more than 50% intact after at least 4 h they are considered as stable enough for diagnostic and therapeutic applications.

TABLE-US-00008 TABLE 8 Results of the plasma stability assay Protein % intact compound remaining after precipita- 4/24 h incubation Com- tion Human Mouse Rat pound method plasma plasma plasma 3BP-2974 A 92% (4 h) 3BP-2975 A 100% (4 h) 3BP-2976 A 93% (4 h) 3BP-3086 A 79% (4 h) 3BP-3105 A 55% (4 h) 3BP-3168 A 100% (4 h) 3BP-3177 A 79% (4 h) 3BP-3181 A 100% (4 h) 3BP-3183 A 98% (4 h) 3BP-3187 A 100% (4 h) 3BP-3188 A 97% (4 h) 3BP-3189 A 100% (4 h) 3BP-3190 A 88% (4 h) 3BP-3191 A 100% (4 h) 3BP-3196 A 87% (4 h) 3BP-3202 A 78% (4 h) 3BP-3203 A 100% (4 h) 3BP-3210 A 100% (4 h) 3BP-3211 A 85% (4 h) 3BP-3212 A 80% (4 h) 3BP-3275 A 94% (4 h) 3BP-3319 A 100% (4 h) 3BP-3320 A 75% (4 h) 3BP-3321 A 94% (4 h) 3BP-3397 A 100% (24 h) 92% (24 h) 3BP-3398 A 99% (24 h) 94% (24 h) 3BP-3407 A 100% (24 h) 79% (24 h) 100% (24 h) 3BP-3426 B 73% (24 h) 3BP-3554 B 100% (24 h) 85% (24 h) 100% (24 h) 3BP-3555 B 88% (24 h) 3BP-3590 B 94% (24 h) 100% (24 h) 100% (24 h) 3BP-3623 B 100% (24 h) 100% (24 h) 100% (24 h) 3BP-3624 B 100% (24 h) 100% (24 h) 100% (24 h)

Example 30: FACS Binding Assay

[0867] In order to determine binding of compounds according to the present invention to FAP-expressing cells, a competitive FACS binding assay was established.

[0868] FAP-expressing human WI-38 fibroblasts (ECACC) were cultured in EMEM including 15% fetal bovine serum, 2 mM L-Glutamine and 1% Non-essential amino acids. Cells were detached with Accutase (Biolegend, #BLD-423201) and washed in FACS buffer (PBS including 1% FBS). Cells were diluted in FACS buffer to a final concentration of 100.000 cells per ml and 200 μl of the cell suspension are transferred to a u-shaped non-binding 96-well plate (Greiner). Cells were washed in ice-cold FACS buffer and incubated with 3 nM of Cy5-labeled compound (H-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-Ttds-Lys(Cy5SO3)-NH2) in the presence of increasing concentrations of peptides at 4° C. for 1 hour. Cell were washed twice with FACS buffer and resuspended in 200 μl FACS buffer. Cells were analyzed in an Attune NxT flow cytometer. Median fluorescence intensities (Cy5 channel) was calculated by Attune NxT software and plotted against peptide concentrations. Four parameter logistic (4PL) curve fitting and pIC50 calculations were performed using ActivityBase software. The results of this assay as well as the ones of the FAP protease activity assay as subject to Example 31 for each compound according to the present invention are presented in Table 9 (shown in Example 31). pIC50 category A stands for pIC50 values >8.0, category B for pIC50 values between 7.1 and 8.0, category C for pIC50 values between 6.1 and 7.0 and category D for pIC50 values ≤6.0.

Example 31: FAP Protease Activity Assay

[0869] In order to determine the inhibitory activity of the peptides of example 13, a FRET-based FAP protease activity assay was established.

[0870] Recombinant human FAP (R&D systems, #3715-SE) was diluted in assay buffer (50 mM Tris, 1 M NaCl, 1 mg/mL BSA, pH 7.5) to a concentration of 3.6 nM. 25 μl of the FAP solution was mixed with 25 μl of a 3-fold serial dilution of the test compounds and incubated for 5 min in a white 96-well ProxiPlate (Perkin Elmer). As specific FAP substrate the FRET-peptide HiLyteFluor™ 488—VS(D-)P SQG K(QXL® 520)-NH2 was used (Bainbridge, et al., Sci Rep, 2017, 7: 12524). 25 μL of a 30 μM substrate solution, diluted in assay buffer, was added. All solutions were equilibrated at 37° C. prior to use. Substrate cleavage and increase in fluorescence (excitation at 485 nm and emission at 538 nm) was measured in a kinetic mode for 5 minutes at 37° C. in a SPECTRAmax M5 plate reader. RFU/sec was calculated by SoftMax Pro software and plotted against peptide concentration. Four parameter logistic (4PL) curve fitting and pIC50 calculations were performed using ActivityBase software. The results of this assay for each compound according to the present invention are given in Table 9. pIC50 category A stands for pIC50 values >8.0, category B for pIC50 values between 7.1 and 8.0, category C for pIC50 values between 6.1 and 7.0 and category D for pIC50 values ≤6.0.

[0871] As evident from Table 9, the compounds of the present invention show surprisingly superior results in both the FACS Binding assay and the FAP protease activity assay.

[0872] In addition to this one can easily find SAR-data which demonstrates that compounds with conjugated chelator are of very similar activity to compounds without chelator but similar peptide sequence. For instance, 3BP-3168 and 3BP-3169 possess chelator and linker at the C-terminus (DOTA-Ttds-Nle/Met) and are in the highest activity categories of pIC.sub.50>8. Corresponding compounds without chelator and linker at the N-Terminus (3BP-2974 with N-terminal Hex-, 3BP-2975 with N-terminal Ac-Met and 3BP-2976 with N-terminal H-met) exhibit all similar activity compared to the chelator comprising compounds 3BP-3168 and 3BP-3169.

[0873] This means that the activity data from chelator free compounds is predictive for the activity of the chelator comprising compounds. This phenomenon is additionally also observed if the chelator is conjugated to the compounds of invention according to the other two specified possibilities. Examples for chelator attachment to the C-terminus compared to corresponding compounds without chelator show the same trends and are 3BP-3105 vs. 3BP-2974, 3BP-3395 or 3BP-3397 vs. 3BP-3476 and examples for the attachment of the chelator to Y.sub.c vs. corresponding compounds without chelator are 3BP-3407 vs. 3B-3476 or 3BP-3426 vs. 3BP-3476.

TABLE-US-00009 TABLE 9  Compound ID, sequence, exact calculated mass, exact mass found, retention time in minutes as determined by HPLC and pIC50 category of FACS binding and FAP activity assay Exact Exact pIC50 pIC50 Mass Mass R.sub.t Category Category ID Sequence (calc) (found) (HPLC) (FACS) (Activity) 3BP- H-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 2354.036 2354.046 5.51 A A 2881 Asp-His-Phe-Arg-Asp-Ttds-Lys(Bio)-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1664.712 1664.718 7.19 A A 2974 Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1739.689 1739.692 6.12 A A 2975 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- H-met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1697.679 1697.679 5.58 A A 2976 Asp-His-Phe-Arg-Asp-NH2 3BP- DOTA-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 2065.903 2065.903 5.44 C C 3088 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 2481.171 2481.171 6.78 A A 3105 Asp-His-Phe-Arg-Asp-Ttds-Lys(DOTA)-NH2 3BP- DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu- 2368.087 2368.093 6.00 A A 3168 Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- DOTA-Ttds-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu- 2386.043 2386.050 5.74 A A 3169 Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- DOTA-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 2083.859 2083.852 5.37 C C 3170 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- DOTA-Ttds-Phe-[Cys(3MeBn)-Pro-Pro-Thr-Glu- 2402.071 2402.075 6.00 B B 3171 Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- DOTA-Ttds-Leu-[Cys(3MeBn)-Pro-Pro-Thr-Glu- 2368.087 2368.091 5.90 A A 3172 Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- DOTA-Ttds-Glu-[Cys(3MeBn)-Pro-Pro-Thr-Glu- 2384.045 2384.049 5.19 B B 3173 Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- DOTA-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1952.819 1952.822 4.86 C C 3174 Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1739.689 1739.696 5.85 A A 3175 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-pro-Pro-Thr-Glu-Phe- 1739.689 1739.693 6.20 C C 3176 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-pro-Thr-Glu-Phe- 1739.689 1739.689 5.85 B B 3177 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-thr-Glu-Phe- 1739.689 1739.692 5.61 B B 3178 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-glu-Phe- 1739.689 1739.692 5.98 B C 3179 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-phe- 1739.689 1739.693 5.97 C C 3180 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Metqcys(3MeBn)-Pro-Pro-Thr-Glu-Phe-cys]- 1739.689 1739.695 6.24 B B 3181 Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1739.689 1739.695 6.12 B B 3182 cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1739.689 1739.694 6.00 B B 3183 Cys]-asp-His-Phe-Arg-Asp-NH2 3BP- Ac-met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1739.689 1739.695 6.34 A A 3187 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1753.705 1753.716 5.87 A A 3188 Cys]-Asp-His-Nmf-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1751.689 1751.697 5.71 A A 3189 Cys]-Asp-His-Tic-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1751.689 1751.701 6.38 A A 3190 Cys]-Asp-His-Aic-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1740.685 1740.696 5.00 A A 3191 Cys]-Asp-His-Ppa-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1740.685 1740.696 5.08 A A 3192 Cys]-Asp-His-Mpa-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Thi-Cys]- 1745.646 1745.650 6.03 A A 3193 Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1695.700 1695.703 6.16 B B 3194 Cys]-Ala-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1673.668 1673.670 6.97 A B 3195 Cys]-Asp-Ala-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1663.658 1663.661 5.43 A A 3196 Cys]-Asp-His-Ala-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1654.625 1654.634 6.51 C C 3197 Cys]-Asp-His-Phe-Ala-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1695.700 1695.711 6.30 A A 3198 Cys]-Asp-His-Phe-Arg-Ala-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1468.561 1468.570 6.64 C B 3199 Cys]-Asp-His-Phe-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1624.663 1624.669 6.31 A A 3200 Cys]-Asp-His-Phe-Arg-NH2 3BP- Ac-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1608.649 1608.659 5.82 A A 3202 Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1753.705 1753.705 6.47 A A 3203 Cys]-Asp-His-Amf-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Aib-Pro-Thr-Glu-Phe- 1727.689 1727.700 6.51 B B 3204 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1739.689 1739.694 6.10 A A 3210 Cys]-Asp-his-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1739.689 1739.692 5.77 A A 3211 Cys]-Asp-His-phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1739.689 1739.692 5.88 A A 3212 Cys]-Asp-His-Phe-arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 1739.689 1739.693 6.16 A A 3213 Cys]-Asp-His-Phe-Arg-asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Gly-Pro-Thr-Glu-Phe- 1699.658 1699.662 5.71 A A 3214 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-ala-Pro-Thr-Glu-Phe- 1713.674 1713.677 5.99 C C 3215 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Oic-Pro-Thr-Glu-Phe- 1793.736 1793.739 6.91 C C 3216 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- Ac-Met-[Cys(3MeBn)-Pro-Oic-Thr-Glu-Phe- 1793.736 1793.740 6.83 C C 3217 Cys]-Asp-His-Phe-Arg-Asp-NH2 3BP- DOTA-Bal-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 2037.871 2037.875 4.71 B B 3264 Cys]-Asp-His-Nmf-Arg-Asp-NH2 3BP- DOTA-Inp-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 2077.903 2077.902 4.83 C C 3265 Cys]-Asp-His-Nmf-Arg-Asp-NH2 3BP- DOTA-Ahx-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe- 2079.918 2079.923 4.95 C C 3266 Cys]-Asp-His-Nmf-Arg-Asp-NH2 3BP- DOTA-O2O-[Cys(3MeBn)-Pro-Pro-Thr-Glu- 2111.908 2111.909 4.93 C C 3267 Phe-Cys]-Asp-His-Nmf-Arg-Asp-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 2380.160 2380.167 6.57 A A 3275 Asp-His-Nmf-Arg-Ttds-Lys(DOTA)-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 2366.144 2366.151 6.47 A A 3276 Asp-His-phe-Arg-Ttds-Lys(DOTA)-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 2367.139 2367.150 5.79 A A 3277 Asp-His-Ppa-arg-Ttds-Lys(DOTA)-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 994.429 994.432 7.59 C B 3287 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1109.456 1109.458 7.42 A A 3288 Asp-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1265.557 1265.562 7.30 A A 3299 Asp-Arg-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1350.610 1350.611 7.29 A A 3300 Asp-Gab-Arg-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1398.610 1398.616 7.38 A A 3301 Asp-Pamb-Arg-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1390.641 1390.641 7.21 A A 3302 Asp-Cmp-Arg-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1283.583 1283.588 7.68 B A 3303 Pamb-Arg-NH2 3BP- DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu- 1697.804 1697.810 5.81 B B 3319 Phe-Cys]-NH2 3BP- DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu- 1812.831 1812.841 5.75 B A 3320 Phe-Cys]-Asp-NH2 3BP- DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu- 2101.985 2101.993 5.49 A A 3321 Phe-Cys]-Asp-Pamb-Arg-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1398.610 1398.614 7.40 A A 3324 Asp-Mamb-Arg-NH2 3BP- Hex-[Cys(3MeBn)-Gly-Pro-Thr-Glu-Phe-Cys]- 954.398 954.402 7.32 C B 3345 NH2 3BP- Hex-[Cys(3MeBn)-Ala-Pro-Thr-Glu-Phe-Cys]- 968.414 968.415 7.46 D C 3346 NH2 3BP- Hex-[Cys(3MeBn)-Nmg-Pro-Thr-Glu-Phe-Cys]- 968.414 968.416 7.37 C B 3347 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Ala-Phe-Cys]- 936.424 936.426 7.75 D D 3348 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 993.445 993.449 7.41 B A 3349 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Ala-Cys]- 918.398 918.398 6.49 D C 3350 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Pen]- 1022.461 1022.463 7.84 D C 3351 NH2 3BP- Hex-[Cys(3MeBn)-Pro-4Tfp-Thr-Glu-Phe-Cys]- 1012.420 1012.422 7.72 C B 3352 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Eay-Thr-Glu-Phe-Cys]- 1070.461 1070.464 9.10 D C 3353 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Ala-Glu-Phe-Cys]- 964.419 964.418 7.63 D D 3354 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Opc-Glu-Phe-Cys]- 1113.478 1113.480 7.63 D C 3355 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Moo-Phe-Cys]- 1028.417 1028.419 7.75 D D 3356 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Nme-Phe-Cys]- 1008.445 1008.448 7.82 D D 3357 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Nmf-Cys]- 1008.445 1008.445 8.12 D C 3358 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Tic-Cys]- 1006.429 1006.431 8.11 D C 3359 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Nphe-Cys]- 994.429 994.432 7.85 D D 3360 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-1Ni-Cys]- 1044.445 1044.448 8.50 B B 3361 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-2Ni-Cys]- 1044.445 1044.449 8.46 C C 3362 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Bip-Cys]- 1070.461 1070.464 9.04 D D 3363 NH2 3BP- Hex-[Cys(3MeBn)-Pro-4Dfp-Thr-Glu-Phe-Cys]- 1030.410 1030.414 8.01 D C 3365 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Hyp-Thr-Glu-Phe-Cys]- 1010.424 1010.428 7.18 B B 3366 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Tap-Thr-Glu-Phe-Cys]- 1009.440 1009.445 6.87 D C 3367 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Ocf-Cys]- 1028.390 1028.394 7.95 C B 3368 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Pcf-Cys]- 1028.390 1028.394 8.14 C C 3369 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 995.413 995.417 7.79 B B 3370 OH 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1066.450 1066.453 7.58 A B 3371 Bal-OH 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Orn(Ac)-Glu-Phe- 1049.471 1049.475 7.33 D C 3372 Cys]-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1924.931 1924.943 6.60 A A 3395 Asp-Ttds-Lys(DOTA)-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]- 1925.915 1925.916 6.73 A A 3396 Asp-Ttds-Lys(DOTA)-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1522.720 1522.714 6.69 A A 3397 Bhk(DOTA)-OH 3BP- DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Gln- 1768.842 1768.842 5.72 A A 3398 Phe-Cys]-Bal-OH 3BP- DOTA-Ttds-Hci-[Cys(3MeBn)-Pro-Pro-Thr-Gln- 1826.858 1826.858 4.78 D D 3399 Phe-Cys]-Bal-OH 3BP- DOTA-Ttds-Hgl-[Cys(3MeBn)-Pro-Pro-Thr-Gln- 1796.873 1796.873 6.58 D B 3400 Phe-Cys]-Bal-OH 3BP- DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Gln- 1811.847 1811.855 5.62 A A 3401 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1579.741 1579.742 6.61 A A 3403 Asp-Ape-NH-DOTA' 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1881.926 1881.933 6.73 A A 3404 Asp-Ttds-Ape-NH-DOTA' 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln- 1592.737 1592.737 5.70 A A 3407 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Trp-Cys]- 1032.456 1032.457 7.58 B B 3408 NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Otf-Cys]- 1061.433 1061.437 8.08 B A 3409 NH2 3BP- Oct-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1136.503 1136.508 8.46 B B 3417 Asp-NH2 3BP- Phb-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1156.472 1156.475 7.73 C C 3418 Asp-NH2 3BP- [3MeBn-Spa-Pro-Pro-Thr-Gln-Phe-Cys]-Asp- 995.388 995.392 6.05 C C 3419 NH2 3BP- PentyINH-urea-[Cys(3MeBn)-Pro-Pro-Thr-Gln- 1123.483 1123.485 7.22 B A 3425 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1583.682 1583.692 5.87 A A 3426 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu(NH-Apr- 1551.710 1551.713 6.57 D D 3472 DOTA')-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu(NH-Apr- 1696.784 1696.793 6.64 C C 3473 O2O-DOTA')-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1108.472 1108.476 7.24 A A 3476 Asp-NH2 3BP- Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1824.904 1824.922 6.66 A A 3489 Bhk(DOTA-Ttds)-OH 3BP- Pentyl-SO2-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe- 1144.439 1144.442 7.79 A A 3514 Cys]-Asp-NH2 3BP- Hex-[Cys(2Lut)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp- 1109.467 1109.469 5.54 A A 3518 NH2 3BP- Hex-[Cys(3Lut)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp- 1109.467 1109.469 5.27 A A 3519 NH2 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1469.639 1469.640 5.89 A A 3554 Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln- 1478.694 1478.699 5.37 B A 3555 Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-NH))-Pro-Pro-Thr-Gln- 1523.679 1523.669 5.71 B B 3556 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(InDOTA-PP))-Pro-Pro-Thr- 1702.617 1702.622 5.59 A A 3590 Gln-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(LuDOTA-PP))-Pro-Pro-Thr- 1764.654 1764.654 5.65 A A 3591 Gln-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(GaDOTA-PP))-Pro-Pro-Thr- 1658.639 1658.644 5.75 A A 3592 Gln-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr- 1579.520 1579.524 5.75 A A 3623 Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(LuDOTA-AET))-Pro-Pro-Thr- 1641.557 1641.560 5.81 A A 3624 Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1519.655 1519.667 5.64 A A 3650 1Ni-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1540.676 1540.686 5.81 A A 3651 Phe-Cys]-Bal-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1468.655 1468.667 5.85 A A 3652 Phe-Cys]-NH2 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Glu- 1469.639 1469.639 5.96 A A 3653 Phe-Cys]-NH2 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1425.649 1425.661 6.16 A A 3654 Phe-AET 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1526.661 1526.665 5.88 A A 3656 Phe-Cys]-Gly-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1554.692 1554.697 5.98 A A 3657 Phe-Cys]-Gab-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1556.671 1556.670 5.78 A A 3658 Phe-Cys]-Ser-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1540.676 1540.682 5.88 A A 3659 Phe-Cys]-Nmg-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1630.723 1630.728 6.85 A A 3660 Phe-Cys]-Bhf-OH 3BP- Hex-[Cys(tMeBn(EuDOTA-PP))-Pro-Pro-Thr- 1740.633 1740.636 5.72 A A 3661 Gln-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(EuDOTA-AET))-Pro-Pro-Thr- 1617.540 1617.541 5.83 A A 3662 Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1470.635 1470.638 4.84 A A 3664 Mpa-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1584.666 1584.666 5.83 A A 3665 Phe-Cys]-Asp-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Nmg-Pro-Thr- 1443.624 1443.624 5.84 A A 3678 Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Hyp-Thr- 1485.634 1485.645 5.69 A A 3679 Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1537.627 1537.626 6.46 A A 3680 Off-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1583.682 1583.697 5.84 A A 3681 Phe-Cys]-asp-NH2 3BP- Ac-met-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr- 1544.617 1544.633 4.97 B B 3682 Gln-Phe-Cys]-OH 3BP- Pentyl-SO2-[Cys(tMeBn(DOTA-AET))-Pro-Pro- 1505.606 1505.610 6.23 A A 3690 Thr-Gln-Phe-Cys]-OH 3BP- Pentyl-SO2-[Cys(tMeBn(DOTA-AET))-Pro-Pro- 1506.590 1506.593 6.40 A B 3691 Thr-Glu-Phe-Cys]-OH 3BP- Pentyl-SO2-[Cys(tMeBn(DOTA-PP))-Pro-Pro- 1628.704 1628.706 5.99 A A 3692 Thr-Gln-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(Cy5SO3-PP))-Pro-Pro-Thr- 1793.851 1793.850 8.94 B 3693 Gln-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(Cy5SO3-AET))-Pro-Pro-Thr- 1670.754 1670.752 9.58 C 3694 Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr- 1578.536 1578.539 5.60 A A 3712 Gln-Phe-Cys]-NH2 3BP- Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr- 1535.530 1535.533 6.01 A A 3713 Gln-Phe-AET 3BP- Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr- 1636.541 1636.546 5.60 A A 3714 Gln-Phe-Cys]-Gly-OH 3BP- Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr- 1650.557 1650.569 5.64 A A 3715 Gln-Phe-Cys]-Nmg-OH 3BP- Hex-[Cys(tMeBn(InDOTA-AET))-Nmg-Pro-Thr- 1553.504 1553.517 5.69 A A 3716 Gln-Phe-Cys]-OH 3BP- Pentyl-SO2-[Cys(tMeBn(InDOTA-PP))-Pro-Pro- 1738.584 1738.588 5.97 A A 3717 Thr-Gln-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1539.692 1539.691 5.66 A A 3736 Phe-Cys]-Bal-NH2 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1539.692 1539.690 5.70 A A 3737 Phe-Cys]-Nmg-NH2 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Ala- 1535.715 1535.721 5.88 C C 3739 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Nmg-Pro-Thr- 1442.640 1442.640 5.66 A A 3744 Gln-Phe-Cys]-NH2 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Ala-Gln- 1562.726 1562.732 5.44 C C 3745 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Ala-Ala- 1505.705 1505.705 5.62 D C 3746 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys(3MeBn)-Nlys-Pro-Thr-Gln-Phe-Cys]- 1024.487 1024.490 6.28 D D 3747 NH2 3BP- Hex-[Cys(3MeBn)-Nphe-Pro-Thr-Gln-Phe-Cys]- 1043.461 1043.462 8.64 D D 3748 NH2 3BP- Hex-[Cys(3MeBn)-Nleu-Pro-Thr-Gln-Phe-Cys]- 1009.477 1009.479 8.32 D D 3749 NH2 3BP- H-Ahx-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1008.456 1008.456 4.77 D D 3759 NH2 3BP- H-Ava-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 994.440 994.441 4.66 D D 3760 NH2 3BP- H-Gab-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe- 980.425 980.425 4.60 D D 3761 Cys]-NH2 3BP- 4Pya-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 1014.409 1014.415 4.74 D C 3762 NH2 3BP- Ac-Hse-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe- 1038.430 1038.430 4.83 D C 3763 Cys]-NH2 3BP- Ac-Aad-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe- 1080.441 1080.440 5.11 D D 3764 Cys]-NH2 3BP- HO-Glutar-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe- 1009.404 1009.403 5.33 C C 3765 Cys]-NH2 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 1455.660 1455.666 5.91 A A 3767 Phe-Cysol] 3BP- Hex-[Cys(tMeBn(InDOTA-PP))-Pro-Pro-Thr- 1588.574 1588.579 5.30 A A 3770 Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Nmg-Pro-Thr-Gln- 1452.678 1452.678 5.12 A A 3771 Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Pro-Thr-Pro-Phe- 1592.737 1592.759 5.35 D D 3854 Gln-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Phe-Gln-Thr-Pro- 1592.737 1592.737 5.67 D D 3855 Pro-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Thr-Gln-Pro-Phe- 1592.737 1592.749 5.10 D D 3856 Pro-Cys]-Asp-NH2 3BP- Hex-[Cys(tMeBn(DOTA-PP))-Pro-Gln-Phe-Pro- 1592.737 1592.737 5.37 C C 3857 Thr-Cys]-Asp-NH2 3BP- H2NSO2-But-[Cys(3MeBn)-Pro-Pro-Thr-Gln- 1044.387 1044.401 5.18 D D 3860 Phe-Cys]-NH2 3BP- Hex-[Cys(tMeBn(GaDOTA-AET))-Pro-Pro-Thr- 1535.541 1535.541 6.58 A A 3949 Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(H-O2O-PP))-Pro-Pro-Thr- 1351.631 1351.648 6.1 A A 3967 Gln-Phe-Cys]-Asp-NH2 3BP- H-Ahx-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln- 1538.751 1538.758 6.3 A A 3980 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys-(tMeBn(H-AET))-Pro-Pro-Thr-Gln- 1197.502 1197.508 6.7 B A 3981 Phe-Cys]-Asp-NH2 3BP- Hex-[Cys-(tMeBn(H-O2O-AET))-Pro-Pro-Thr- 1342.576 1342.578 6.5 A A 4003 Gln-Phe-Cys]-Asp-NH2 3BP- H-Ahx-Ttds-Nle-[Cys-(tMeBn(DOTA-PP))-Pro- 2023.016 2023.029 5.2 B A 4004 Pro-Thr-Gln-Phe-Cys]-Asp-NH2 3BP- Hex-[Cys-(tMeBn(N4Ac-AET))-Pro-Pro-Thr-Gln- 1269.607 1269.612 6.0 A A 4063 Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(N4Ac-O2O-AET))-Pro-Pro- 1414.681 1414.691 6.0 A A 4088 Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(H-AET))-Pro-Pro-Thr-Gln- 1083.459 1083.472 6.9 C B 4089 Phe-Cys]-OH 3BP- Hex-[D-Cys-(tMeBn(DOTA-AET))-Pro-Pro-Thr- 1469.639 1469.646 6.3 A A 4109 Gln-Phe-Cys]-OH 3BP- Hex-[D-Cys-(tMeBn(DOTA-AET))-Pro-Pro-Thr- 1469.639 1469.647 6.6 B B 4110 Gln-Phe-D-Cys]-OH 3BP- Hex-[Cys-(tMeBn(DOTA-AET))-Pro-Pro-Thr- 1469.639 1469.646 6.0 B B 4111 Gln-Phe-D-Cys]-OH 3BP- Hex-[Cys-(tMeBn(ReON4Ac-O2O-AET))-Pro- 1612.606 1612.620 6.6 A A 4147 Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(ReON4Ac-AET))-Pro-Pro- 1467.532 1467.543 6.8 A A 4148 Thr-Gln-Phe-Cys]-OH 3BP- N4Ac-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu- 1498.756 1498.765 5.8 A A 4161 Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(NODAGA-AET))-Pro-Pro-Thr- 1440.613 1440.623 6.8 A A 4162 Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(N4Ac-PP))-Pro-Pro-Thr-Gln- 1278.662 1278.669 5.5 A A 4168 Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(N4Ac-O2Oc-PP))-Pro-Pro- 1423.736 1423.741 5.4 B A 4169 Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(Bio-Ttds-Ttds-Ttds-Ttds- 2518.273 2518.291 7.3 B B 4170 AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(H-PP))-Pro-Pro-Thr-Gln-Phe- 1092.514 1092.524 5.8 B B 4181 Cys]-OH 3BP- Hex-[Cys(tMeBn(ATT0488-AET))-Pro-Pro-Thr- 1654.531 1654.530 6.9 B B 4182 Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(GaNODAGA-AET))-Pro-Pro- 1506.515 1506.522 6.6 A A 4184 Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]- 994.429 994.431 7.9 B B 4186 OH 3BP- Hex-[Cys-(tMeBn(DTPA-AET))-Pro-Pro-Thr- 1458.587 1458.594 6.5 B B 4214 Gln-Phe-Cys]-OH 3BP- N4Ac-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln- 1497.772 1497.780 5.7 B A 4219 Phe-Cys]-OH 3BP- N4Ac-APAc-Nle-[Cys-(3MeBn)-Pro-Pro-Thr- 1336.667 1336.674 5.4 D D 4220 Glu-Phe-Cys]-OH 3BP- N4Ac-PEG6-Nle-[Cys-(3MeBn)-Pro-Pro-Thr- 1531.767 1531.779 5.9 B B 4221 Glu-Phe-Cys]-OH 3BP- N4Ac-Glu-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr- 1627.799 1627.810 5.7 B B 4222 Glu-Phe-Cys]-OH 3BP- N4Ac-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu- 1499.752 1499.768 4.6 C C 4223 Ppa-Cys]-OH 3BP- Hex-[Cys-(tMeBn(DTPA-O2O-AET))-Pro-Pro- 1603.661 1603.656 6.6 B B 4224 Thr-Gln-Phe-Cys]-OH 3BP- N4Ac-O2O-Nle-[Cys-(3MeBn)-Pro-Pro-Thr- 1341.646 1341.642 5.4 D C 4228 Glu-Phe-Cys]-OH 3BP- DTPA-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu- 1687.736 1687.749 6.4 C B 4229 Phe-Cys]-OH 3BP- N4Ac-gGlu-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu- 1325.615 1325.610 5.5 D D 4230 Phe-Cys]-OH 3BP- N4Ac-Ttds-Glu(AGLU')-Nle-[Cys-(3MeBn)-Pro- 1790.883 1790.909 5.4 D D 4231 Pro-Thr-Glu-Phe-Cys]-OH 3BP- N4Ac-Ttds-Glu-[Cys-(3MeBn)-Pro-Pro-Thr-Glu- 1514.715 1514.715 5.0 C D 4233 Phe-Cys]-OH 3BP- N4Ac-Efa-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu- 1430.640 1430.643 5.7 B B 4243 Phe-Cys]-OH 3BP- N4Ac-gGlu-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln- 1324.631 1324.635 5.4 D D 4244 Phe-Cys]-OH 3BP- N4Ac-gGlu-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro- 1626.815 1626.821 5.7 B B 4245 Thr-Gln-Phe-Cys]-OH 3BP- N4Ac-Glu(AGLU')-Ttds-Nle-[Cys-(3MeBn)-Pro- 1789.899 1789.901 5.5 B B 4246 Pro-Thr-Gln-Phe-Cys]-OH 3BP- N4Ac-gGlu-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro- 1627.799 1627.805 5.9 B B 4247 Thr-Glu-Phe-Cys]-OH 3BP- N4Ac-Ttds-Glu(AGLU')-Nle-[Cys-(3MeBn)-Pro- 1789.899 1789.895 5.3 D D 4248 Pro-Thr-Gln-Phe-Cys]-OH 3BP- N4Ac-Glu(AGLU')-Ttds-Nle-[Cys-(3MeBn)-Pro- 1790.883 1790.909 5.7 B B 4249 Pro-Thr-Glu-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(DOTA-AET))-Pro-Pro-Thr- 1470.623 1470.626 6.4 A B 4250 Glu-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(NODAGA-O2O-AET))-Pro- 1585.687 1585.689 6.7 A A 4251 Pro-Thr-Gln-Phe-Cys]-OH 3BP- N4Ac-Glu(AGLU')-Glu(AGLU')-Ttds-Nle-[Cys- 2082.026 2082.030 5.6 C B 4265 (3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH 3BP- N4Ac-Glu(AGLU″)-Glu(AGLU')-Ttds-Nle-[Cys- 2083.010 2083.013 5.6 B B 4266 (3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(CuDOTA-AET))-Pro-Pro-Thr- 1530.553 1530.562 6.5 A A 4293 Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(N4Ac-Ttds-AET))-Pro-Pro- 1571.791 1571.807 5.9 A A 4299 Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(N4Ac-PEG6-AET))-Pro-Pro- 1604.802 1604.816 6.1 B A 4300 Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(H-SAc-Ser-Ser-Ser-AET))- 1418.538 1418.553 6.8 B B 4301 Pro-Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(H-Asp-Asp-Cys-Ttds-AET))- 1718.706 1718.723 6.8 C B 4302 Pro-Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(H-Asp-Asp-Cys-AET))-Pro- 1416.522 1416.536 6.6 C B 4303 Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(H-SAc-Ser-Ser-Ser-Ttds- 1720.722 1720.730 6.9 B B 4308 AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(DTPA2-AET))-Pro-Pro-Thr- 1458.587 1458.597 6.5 B B 4309 Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(NOTA-AET))-Pro-Pro-Thr- 1368.592 1368.600 6.7 A A 4310 Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(H-HYNIC-AET))-Pro-Pro-Thr- 1218.502 1218.505 6.9 B A 4342 Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(ZnDOTA-AET))-Pro-Pro-Thr- 1531.553 1531.558 6.4 A A 4343 Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(NOTA-Ttds-AET))-Pro-Pro- 1670.776 1670.777 6.8 A A 4344 Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(DTPA2-Ttds-AET))-Pro-Pro- 1760.771 1760.773 6.7 C B 4352 Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(DTPA2-PEG6-AET))-Pro- 1793.781 1793.786 6.8 B B 4353 Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys-(tMeBn(DTPABzI-Glutar-AET))-Pro- 1677.676 1677.688 7.0 C C 4366 Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(LuDOTA-AET))-Pro-Pro-Thr- 2943.026 2943.056 5.6 A A 4372 Gln-Phe-Cys]-Asp-Gab-Arg-Ttds-Lys(AF488)- NH2 3BP- Hex-[Cys(tMeBn(LuDOTA-AET))-Pro-Pro-Thr- 3547.394 3547.431 5.7 B A 4373 Gln-Phe-Cys]-Asp-Gab-Arg-Ttds-Ttds-Ttds- Lys(AF488)-NH2 3BP- Hex-[Cys-(tMeBn(H-HYNIC--Ttds--AET))-Pro- 1520.687 1520.685 6.8 A A 4376 Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex--[C(tMeBn(PCTA-AET))-Pro-Pro-Thr-Gln- 1445.618 1445.635 6.5 A A 4379 Phe-Cys]-OH 3BP- Hex--[C(tMeBn(NOPO-AET))-Pro-Pro-Thr-Gln- 1560.579 1560.596 6.3 A A 4380 Phe-Cys]-OH 3BP- Hex--[C(tMeBn(HBED-AET))-Pro-Pro-Thr-Gln- 1597.654 1597.669 7.4 B B 4381 Phe-Cys]-OH 3BP- Hex--[C(tMeBn(DATA-AET))-Pro-Pro-Thr-Gln- 1468.644 1468.657 7.0 B B 4382 Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(HBED-PEG6-AET))-Pro-Pro- 1932.849 1932.888 7.4 B B 4383 Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DATA-Ttds-AET))-Pro-Pro- 1770.828 1770.836 7.1 B B 4384 Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(NOPO-Ttds-AET))-Pro-Pro- 1862.763 1862.785 6.5 B B 4385 Thr-Gln-Phe-Cys]-OH 3BP- DOTA-Ttds-Nle-[Cys(tMeBn(DOTA-AET))-Pro- 2173.015 2173.023 5.1 B B 4386 Pro-Thr-Gln-Phe-Cys]-OH 3BP- Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln- 2400.141 2400.173 5.8 A A 4391 Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 3BP- DOTA-Ttds-Nle-[Cys(tMeBn(DOTA-AET))-Pro- 3013.517 3103.535 5.0 B B 4392 Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Lys(DOTA)- NH2 3BP- DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Gln- 2628.307 2628.327 5.7 A A 4393 Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2

Example 32: Surface Plasmon Resonance Assay

[0874] Surface plasmon resonance studies were performed using a Biacore™ T200 SPR system. Briefly, polarized light is directed towards a gold-labeled sensor surface, and minimum intensity reflected light is detected. The angle of reflected light changes as molecules bind and dissociate. The gold-labeled sensor surface is loaded with FAP antibodies bearing FAP target proteins, whereby antibody binding does not occur at the substrate-binding site of FAP. Test compounds are contacted with the loaded surface, and a real-time interaction profile with the FAP ligand is recorded in a sensorgram. In real-time, the association and dissociation of a binding interaction is measured, enabling calculation of association and dissociation rate constants and the corresponding affinity constants. Importantly, a background response is generated due to the difference in the refractive indices of the running and sample buffers, as well as unspecific binding of the test compounds to the flow cell surface. This background is measured and subtracted by running the sample on a control flow cell coated with the same density of capture antibody in the absence of immobilized FAP. Furthermore, baseline drift correction of the binding data is performed, which is caused by slow dissociation of the captured FAP from the immobilized antibody. This drift is measured by injecting running buffer through a flow cell with the antibody and FAP immobilized to the sensor surface.

[0875] Biacore™ CM5 sensor chips were used. Human anti-FAP antibody (MAB3715, R&D systems) was diluted in 10 mM acetate buffer, pH 4.5, to a final concentration of 50 μg/mL. A 150 μL aliquot was transferred into plastic vials and placed into the sample rack of the Biacore™ T200 instrument. Amine Coupling Kit Reagent solutions were transferred into plastic vials and placed into the sample rack: 90 μL of 0.4 M 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 90 μL of 0.1 M N-hydroxysuccinimide (NHS). A 130 μL aliquot of 1 M ethanolamine-HCl, pH 8.5, was transferred into plastic vials and placed into the sample rack. The Biacore™ liquid system was set-up as follows: Separate bottles containing distilled water (1 L), Running Buffer (500 mL), as well as an empty bottle for waste were placed onto the buffer tray. A preinstalled program for immobilization was used, with an immobilization level of 7000 RU. Immobilization was performed at 25° C. The immobilization procedure of anti-FAP antibodies was performed, as described in the Table 10.

TABLE-US-00010 TABLE 10 Immobilization protocol for anti-FAP antibodies used on the CM5 sensor chip. Step Injected solution Contact time Flow rate Surface conditioning 50 mM NaOH 300 s 10 μL/min Surface activation EDC/NHS 420 s 10 μL/min Washing Ethanolamine  90 s 10 μL/min Ligand binding Human/mouse 420 s 10 μL/min antibodies diluted in acetate buffer Washing Running Buffer  40 s 10 μL/min Deactivation of reactive, 1M ethanolamine 420 s 10 μL/min non-ligand bound surface Washing Running Buffer  30 s 10 μL/min

[0876] Human recombinant FAP was diluted in Running Buffer to a final concentration of 20 μg/mL. A 100 μL aliquot of human FAP-Working-Solution was transferred into plastic vials and placed into a sample rack. A 0.5 mM Compound-Stock-Solution was prepared by dissolving each compound in DMSO. For each test compound, Compound-Stock-Solutions were diluted in Running Buffer (HBST) at 500 nM and further diluted with HBST-DMSO Buffer (0.1% DMSO). SPR binding analyses for binary complexes were performed in SCK mode at 25° C. Table 11 describes the protocol for capturing and assessment of the binding kinetics. Following three SCK measurements, a baseline drift was assessed by injecting running buffer through a flow cell, with the antibody and FAP immobilized to the sensor surface.

TABLE-US-00011 TABLE 11 Protocol for assessing the binding kinetics. Contact Flow Step Injected solution time rate Startup cycle as a triple run: Washing HBST-DMSO  60 s 30 μL/min Buffer & surface regeneration 10 mM glycine,  5 s pH 2 Binding target protein FAP 20 μg/mL rhFAP or 600 s  5 μL/min (capturing) 4 μg/mL rmFAP Washing (removal of unbound HBST-DMSO- 2700 s  30 μL/min FAP) Buffer 1. Binding kinetics of test Dilution no. 5 120 s 30 μL/min compound (0.19 nM) 2. Binding kinetics of test Dilution no. 4 120 s 30 μL/min compound (0.78 nM) 3. Binding kinetics of test Dilution no. 3 120 s 30 μL/min compound (3.125 nM) 4. Binding kinetics of test Dilution no. 2 120 s 30 μL/min compound (12.5 nM) 5. Binding kinetics of test Dilution no. 1 120 s 30 μL/min compound (50 nM) Dissociation cycle HBST-DMSO 1800 s  30 μL/min Buffer Regeneration 10 mM glycine,  7 s 30 μL/min pH 2

[0877] For each test compound, SPR raw data in the form of resonance units (RU) were plotted as sensorgrams using the Biacore™ T200 control software. The signal from the blank sensorgram was subtracted from that of the test compound sensorgram (blank corrected). The blank corrected sensorgram was corrected for baseline drift by subtracting the sensorgram of a SCK run without the test compound (running buffer only). The association rate (k.sub.on), dissociation rate (k.sub.off), dissociation constant (K.sub.D), and t.sub.1/2 were calculated from Blank-normalized SPR data using the 1:1 Langmuir binding model from the Biacore™ T200 evaluation software. Raw data and fit results were imported as text files in IDBS. The pK.sub.D value (negative decadic logarithm of dissociation constant) was calculated in the IDBS excel template.

[0878] The results of this assay for a selection of compounds according to the present invention are presented in Table 12. Category A stands for pK.sub.D values >8.0, category B for pK.sub.D values between 7.1 and 8.0, category C for pK.sub.D values between 6.1 and 7.0.

TABLE-US-00012 TABLE 12  Compound ID, sequence and pkD category of Biacore assay pK.sub.D ID Sequence Category 3BP-2974 Hex--C([3MeBn)-PPTEFMHFRD-NH2 A 3BP-2975 Ac-M-C([3MeBn)-PPTEFMHFRD-NH2 A 3BP-3105 Hex--C([3MeBn)-PPTEFMHFRD-Ttds--K(DOTA)--NH2 A 3BP-3168 DOTA--Ttds--Nle--C([3MeBn)-PPTEFQDHFRD-NH2 A 3BP-3202 Ac--C([3MeBn)-PPTEFMHFRD-NH2 A 3BP-3275 Hex--C([3MeBn)-PPTEFMH-Nmf-R-Ttds--K(DOTA)--NH2 A 3BP-3288 Hex--C([3MeBn)-PPTEFM-NH2 A 3BP-3300 Hex--C([3MeBn)-PPTEFM-Gab-R-NH2 A 3BP-3301 Hex--C([3MeBn)-PPTEFM-Pamb-R-NH2 A 3BP-3319 DOTA--Ttds--Nle--C([3MeBn)-PPTEFQ-NH2 B 3BP-3320 DOTA--Ttds--Nle--C([3MeBn)-PPTEFQD-NH2 A 3BP-3321 DOTA--Ttds--Nle--C([3MeBn)-PPTEFQD-Pamb-R-NH2 A 3BP-3324 Hex--C([3MeBn)-PPTEFM-Mamb-R-NH2 A 3BP-3349 Hex--C([3MeBn)-PPTQFQ-NH2 A 3BP-3395 Hex--C([3MeBn)-PPTQFM-Ttds--K(DOTA)--NH2 A 3BP-3396 Hex--C([3MeBn)-PPTEFM-Ttds--K(DOTA)--NH2 A 3BP-3397 Hex--C([3MeBn)-PPTQFQ-Bhk(DOTA)--OH A 3BP-3398 DOTA--Ttds--Nle--C([3MeBn)-PPTQFQ-Bal--OH A 3BP-3401 DOTA--Ttds--Nle--C([3MeBn)-PPTQFQD-NH2 A 3BP-3403 Hex--C([3MeBn)-PPTQFQD-Ape--NH--DOTA A 3BP-3407 Hex--[C(tMeBn(DOTA--PP))-PPTQFQD-NH2 A 3BP-3426 Hex--CatMeBn(DOTA--AET))-PPTQFQD-NH2 A 3BP-3476 Hex--C([3MeBn)-PPTQFM-NH2 A 3BP-3489 Hex--C([3MeBn)-PPTQFQ-Bhk(DOTA--Ttds)--OH A 3BP-3514 Pentyl--SO2--C([3MeBn)-PPTQFM-NH2 A 3BP-3554 Hex--[C(tMeBn(DOTA--AET))-PPTQFC]-OH A 3BP-3555 Hex--CatMeBn(DOTA--PP))-PPTQFC]-OH A 3BP-3590 Hex--CatMeBn(InDOTA--PP))-PPTQFM-NH2 A 3BP-3591 Hex--CatMeBn(LuDOTA--PP))-PPTQFM-NH2 A 3BP-3592 Hex--CatMeBn(GaDOTA--PP))-PPTQFM-NH2 A 3BP-3623 Hex--CatMeBn(InDOTA--AET))-PPTQFC]-OH A 3BP-3624 Hex--CatMeBn(LuDOTA--AET))-PPTQFC]-OH A 3BP-3650 Hex--CatMeBn(DOTA--AET))-PPTQ-1Ni-C]-OH A 3BP-3651 Hex--CatMeBn(DOTA--AET))-PPTQFQ-Bal--OH A 3BP-3652 Hex--CatMeBn(DOTA--AET))-PPTQFQ-NH2 A 3BP-3653 Hex--CatMeBn(DOTA--AET))-PPTEFQ-NH2 A 3BP-3654 Hex--CatMeBn(DOTA--AET))-PPTQF-AET A 3BP-3656 Hex--CatMeBn(DOTA--AET))-PPTQFC]G-OH A 3BP-3657 Hex--CatMeBn(DOTA--AET))-PPTQFQ-Gab--OH A 3BP-3658 Hex--CatMeBn(DOTA--AET))-PPTQFQS-OH A 3BP-3659 Hex--CatMeBn(DOTA--AET))-PPTQFQ-Nmg--OH A 3BP-3660 Hex--CatMeBn(DOTA--AET))-PPTQFQ-Bhf--OH A 3BP-3665 Hex--CatMeBn(DOTA--AET))-PPTQFC]D-OH A 3BP-3678 Hex--[C(tMeBn(DOTA--AET))--Nmg-PTQFC]-OH A 3BP-3679 Hex--[C(tMeBn(DOTA--AET))-P-Hyp-TQFC]-OH A 3BP-3680 Hex--[C(tMeBn(DOTA--AET))-PPTQ-Otf-C]-OH A 3BP-3681 Hex--[C(tMeBn(DOTA--AET))-PPTQFC]d-NH2 A 3BP-3690 Pentyl--SO2--CatMeBn(DOTA--AET))-PPTQFC]-OH A 3BP-3692 Pentyl--SO2--CatMeBn(DOTA--PP))-PPTQFCH2 A 3BP-3712 Hex--[C(tMeBn(InDOTA--AET))-PPTQFC]-NH2 A 3BP-3713 Hex--[C(tMeBn(InDOTA--AET))-PPTQF-AET] A 3BP-3714 Hex--[C(tMeBn(InDOTA--AET))-PPTQFC]G-OH A 3BP-3715 Hex--[C(tMeBn(InDOTA--AET))-PPTQFQ-Nmg--OH A 3BP-3716 Hex--[C(tMeBn(InDOTA--AET))--Nmg-PTQFC]-OH A 3BP-3717 Pentyl--SO2--[C(tMeBn(InDOTA--PP))-PPTQFCH2 A 3BP-3736 Hex--[C(tMeBn(DOTA--AET))-PPTQFQ-Bal--NH2 A 3BP-3737 Hex--[C(tMeBn(DOTA--AET))-PPTQFC]-Nmg--NH2 A 3BP-3907 iHex--[C(tMeBn(DOTA--AET))-PPTQFC]-OH A 3BP-3910 Pent--[C(tMeBn(DOTA--AET))-PPTQFC]-OH A 3BP-3918 Et0Pr--[C(tMeBn(DOTA--AET))-PPTQFC]-OH A 3BP-3940 nBu--CAyl--[C(tMeBn(DOTA--AET))-PPTQFC]-OH A 3BP-3949 Hex--[C(tMeBn(GaDOTA--AET))-PPTQFC]-OH A 3BP-4063 Hex--[C(tMeBn(N4Ac--AET))-PPTQFC]-OH A 3BP-4064 Hex--[C(tMeBn(Cy5SO3--O2O--AET))-PPTQFC]-OH A 3BP-4088 Hex--[C(tMeBn(N4Ac--O2O--AET))-PPTQFC]-OH A 3BP-4147 Hex--[C(tMeBn(ReON4Ac--O2O--AET))-PPTQFC]-OH A 3BP-4148 Hex--[C(tMeBn(ReON4Ac--AET))-PPTQFC]-OH A 3BP-4161 N4Ac--Ttds--Nle--[C(3MeBn)-PPTEFC]-OH A 3BP-4162 Hex--[C(tMeBn(NODAGA--AET))-PPTQFC]-OH A 3BP-4168 Hex--[C(tMeBn(N4Ac--PP))-PPTQFC]-OH A 3BP-4182 Hex--[C(tMeBn(ATT0488--AET))-PPTQFC]-OH B 3BP-4184 Hex--[C(tMeBn(GaNODAGA--AET))-PPTQFC]-OH A 3BP-4219 N4Ac--Ttds--Nle--[C(3MeBn)-PPTQFC]-OH A 3BP-4221 N4Ac--PEG6--Nle--[C(3MeBn)-PPTEFC]-OH A 3BP-4222 N4Ac-E-Ttds--Nle--[C(3MeBn)-PPTEFC]-OH A 3BP-4232 Hex--[C(tMeBn(AF488--Ttds--Ttds--Ttds--Ttds-- C AET))-PPTQFC]-OH 3BP-4246 N4Ac--E(AGLU)--Ttds--Nle--[C(3MeBn)-PPTQFC]-OH A 3BP-4249 N4Ac--E(AGLU)--Ttds--Nle--[C(3MeBn)-PPTEFC]-OH A 3BP-4250 Hex--[C(tMeBn(DOTA--AET))-PPTEFC]-OH A 3BP-4251 Hex--[C(tMeBn(NODAGA--O2O--AET))-PPTQFC]-OH A

Example 33: PREP and DPP4 Protease Activity Assay

[0879] In order to test selectivity of FAP binding peptides toward both PREP and DPP4, protease activity assays were performed analogues to the FAP activity assay described above with following exceptions.

[0880] PREP activity was measured with recombinant human PREP (R&D systems, #4308-SE). As substrate 50 μM Z-GP-AMC (Bachem, #4002518) was used. The DPP4 activity assay was performed in DPP assay buffer (25 mM Tris, pH 8.0). Recombinant human DPP4 was purchased from R&D systems (#9168-SE). 20 μM of GP-AMC (Santa Cruz Biotechnology, #115035-46-6) was used as substrate.

[0881] Fluorescence of AMC (excitation at 380 nm and emission at 460 nm) after cleavage was measured in a kinetic mode for 5 minutes at 37° C. in a SPECTRAmax M5 plate reader. RFU/sec was calculated by SoftMax Pro software and plotted against peptide concentration. Four parameter logistic (4PL) curve fitting and pIC50 calculations were performed using ActivityBase software. The results of this assay for some of the compounds according to the present invention are given in the following Table 13.

TABLE-US-00013 TABLE 13 Results (pIC50 values) of PREP and DPP4 activity assays pIC50 pIC50 ID (PREP) (DPP4) 3BP-2881 <6 <6 3BP-3105 <6 <6 3BP-3168 <6 <6 3BP-3275 <6 <6 3BP-3287 <6 <6 3BP-3319 6.2 <6 3BP-3320 <6 <6 3BP-3321 <6 <6 3BP-3349 <6 <6 3BP-3397 <6 <6 3BP-3398 <6 <6 3BP-3407 <6 <6 3BP-3419 <6 <6 3BP-3426 <6 <6 3BP-3476 <6 <6 3BP-3554 <6 <6

Example 34: Specificity Screen

[0882] The specificity screening was carried out in order to early identify significant off-target interactions of compounds of the present invention. The specificity was tested using a standard battery of assays (“SafetyScreen44™ Panel”) comprising 44 selected targets and compounds binding thereto (referred to as “reference compounds”, Ref. Compounds), recommended by Bowes et al. (Bowes, et al., Nat Rev Drug Discov, 2012, 11: 909). The reference compounds served as positive controls for the respective assays, therefore inhibition is expected to be detected with these reference compounds. The compounds of the invention, however, were not expected to show inhibition in these assays. These binding and enzyme inhibition assays were performed by Eurofins Cerep SA (Celle l'Evescault, France).

[0883] 3BP-3407 and 3BP-3554 were tested at 10 μM. Compound binding was calculated as % inhibition of the binding of a radioactively labeled ligand specific for each target (“% Inhibition of Specific Binding” (3BP-3407) or (3BP-3554), respectively). Compound enzyme inhibition effect was calculated as % inhibition of control enzyme activity.

[0884] Results showing an inhibition or stimulation higher than 50% are considered to represent significant effects of the test compounds. Such effects were not observed at any of the receptors studied which are listed in the following Table 14. The results of this assay are summarized in the following Table 14.

TABLE-US-00014 TABLE 14 Results of the specificity screening (SafetyScreen44 ™ Panel) for 10 μM 3BP-3407 and 10 μM 3BP-3554 % Inhibition of Specific Binding Cerep (3BP- (3BP- Ref Catalog Assay 3407) 3554) Compound Ki Ref [M] Ref Literature Reference A2A (h) (agonist −4 −16 NECA 2.90E−08 4 (Luthin, et al., Mol radioligand) Pharmacol, 1995, 47: 307) alpha 1A (h) 2 −12 WB 4101 2.40E−10 2338 (Schwinn, et al., J Biol (antagonist Chem, radioligand) 1990, 265: 8183) alpha 2A (h) −9 2 yohimbine 2.40E−09 13 (Langin, et al., Eur J (antagonist Pharmacol, radioligand) 1969, 167: 95) beta 1 (h) 4 −13 atenolol 3.40E−07 18 (Levin, et al., J Biol (agonist Chem, radioligand) 2002, 277: 30429) beta 2 (h) 4 8 ICI 118551 1.60E−10 20 (Joseph, et al., (antagonist Naunyn radioligand) Schmiedebergs Arch Pharmacol, 2004, 369: 525) BZD (central) −9 5 diazepam 8.10E−09 28 (Speth, et al., Life Sci, (agonist 1979, 24: 351) radioligand) CB1 (h) (agonist 5 −7 CP 55940 2.10E−09 36 (Rinaldi-Carmona, et radioligand) al., J Pharmacol Exp Ther, 1996, 278: 871) CB2 (h) (agonist 2 −5 WIN 55212- 1.60E−09 37 (Munro, et al., Nature, radioligand) 2 1993, 365:61) CCK1 (CCKA) (h) 24 16 CCK-8s 4.90E−11 39 (Bignon, et al., J (agonist Pharmacol Exp Ther, radioligand) 1999, 289: 742) D1 (h) 0 7 SCH 23390 2.00E−10 44 (Zhou, et al., Nature, (antagonist 1990, 347: 76) radioligand) D2S (h) (agonist 15 −7 7-OH-DPAT 1.30E−09 1322 (Grandy, et al., Proc radioligand) Natl Acad Sci U S A, 1989, 86: 9762) ETA (h) (agonist −18 6 endothelin- 1.50E−11 54 (Buchan, et al., Br J radioligand) 1 Pharmacol, 1994, 112: 1251) NMDA 9 1 CGS 1.40E−07 66 (Sills, et al., Eur J (antagonist 19755 Pharmacol, radioligand) 1991, 192: 19) H1 (h) 11 4 pyrilamine 1.10E−09 870 (Smit, et al., Br J (antagonist Pharmacol, radioligand) 1996, 117: 1071) H2 (h) −5 −16 cimetidine 4.30E−07 1208 (Leurs, et al., Br J (antagonist Pharmacol, radioligand) 1994, 112: 847) MAO-A −5 −25 clorgyline 7.30E−10 443 (Cesura, et al.,Mol (antagonist Pharmacol, radioligand) 1990, 37: 358) M1 (h) 6 8 pirenzepine 2.90E−08 91 (Dorje, et al., J (antagonist Pharmacol Exp Ther, radioligand) 1991, 256: 727) M2 (h) −4 7 Methoctramine 4.80E−08 93 (Dorje, et al., J (antagonist Pharmacol Exp Ther, radioligand) 1991, 256: 727) M3 (h) 10 1 4-DAMP 8.00E−10 95 (Peralta, et al., Embo (antagonist J, 1987, 6: 3923) radioligand) N neuronal alpha −8 −2 nicotine 1.20E−09 3029 (Gopalakrishnan, et 4beta 2 (h) al., J Pharmacol Exp (agonist Ther, 1996, 276: 289) radioligand) delta (DOP) (h) 0 1 DPDPE 1.20E−09 114 (Simonin, et al., Mol (agonist Pharmacol, radioligand) 1994, 46: 1015) kappa (h) (KOP) 7 10 U50488 4.50E−10 4461 (Simonin, et al., Proc (agonist Natl Acad Sci U S A, radioligand) 1995, 92: 7006) mu (MOP) (h) 2 −10 DAMGO 3.70E−10 118 (Wang, et al., FEBS (agonist Lett, 1994, 338:217) radioligand) 5-HT1A (h) −3 −5 8-OH-DPAT 2.20E−10 131 (Mulheron, et al., J Biol (agonist Chem, radioligand) 1994, 269: 12954) 5-HT1B (h) −11 8 Serotonine 6.60E−08 4376 (Maier, et al., J (antagonist Pharmacol Exp Ther, radioligand) 2009, 330: 342) 5-HT2A (h) −2 4 (±)DOI 2.10E−10 471 (Bryant, et al., Life Sci, (agonist 1996, 59: 1259) radioligand) 5-HT2B (h) 2 3 (±)DOI 4.20E−09 1333 (Choi, et al., FEBS (agonist Lett, 1994, 352: 393) radioligand) 5-HT3 (h) 2 4 MDL 72222 6.50E−09 411 (Hope, et al., Br J (antagonist Pharmacol, radioligand) 1996, 118: 1237) GR (h) (agonist −2 0 Dexameth- 1.90E−09 469 (Clark, et al., Invest radioligand) asone Ophthalmol Vis Sci, 1996, 37: 805) AR (h) (agonist 3 −5 Testos- 2.00E−09 933 (Zava, et al., radioligand) terone Endocrinology, 1979, 104: 1007) V1a (h) (agonist 16 1 [d(CH2)51, 1.10E−09 159 (Tahara, et al., Br J radioligand) Tyr(Me)2]- Pharmacol, AVP 1998, 125: 1463) Ca2+ channel (L, 42 54 nitrendipine 1.40E−10 161 (Gould, et al.,Proc dihydropyridine Natl Acad Sci U S A, site) (antagonist 1982, 79: 3656) radioligand) Potassium 2 6 Terfenadine 4.40E−08 4094 (Huang, et al., Assay Channel hERG Drug Dev Technol, (human)- [3H] 2010, 8: 727) Dofetilide KV channel −5 4 alpha - 9.70E−11 166 (Sorensen, et al., Mol (antagonist dendrotoxin Pharmacol, radioligand) 1989, 36: 689) Na+ channel (site −7 14 veratridine 1.20E−05 169 (Brown, J Neurosci, 2) (antagonist 1986, 6: 2064) radioligand) norepinephrine −8 −5 protriptyline 2.30E−09 355 (Pacholczyk, et al., transporter (h) Nature, (antagonist 1991, 350: 350) radioligand) dopamine 12 7 BTCP 6.80E−09 52 (Pristupa, et al., Mol transporter (h) Pharmacol, (antagonist 1994, 45: 125) radioligand) 5-HT transporter −3 −8 imipramine 1.40E−09 439 (Tatsumi, et al., Eur J (h) (antagonist Pharmacol, radioligand) 1999, 368: 277) COX1(h) 10 8 Diclofenac 1.30E−08 4173 (Vanachayangkul, et al., Enzyme Res, 2012, 2012:416062) COX2(h) −14 −22 NS398 5.40E−08 4186 (Vanachayangkul, et al., Enzyme Res, 2012, 2012:416062) PDE3A (h) −3 −37 milrinone 1.00E−06 4072 (Maurice, et al., Nat Rev Drug Discov, 2014, 13: 290) PDE4D2 (h) −5 −4 Ro 20-1724 2.30E−07 4077 (Maurice, et al., Nat Rev Drug Discov, 2014, 13: 290) Lck kinase (h) 10 −4 Staurosporine 2.30E−08 2906 (Park, et al.,Anal Biochem, 94) Acetylcholin- −6 1 Galanthamine 7.00E−07 363 (Ellman, et al., esterase (h) Biochem Pharmacol, 1999, 269: 1961, 7: 88)

[0885] Additionally, a specificity screen for proteases was performed by BPS Biosciences to further determine the specificity of the compounds of the invention (Turk, Nat Rev Drug Discov, 2006, S: 785; Overall, et al., Nat Rev Cancer, 2006, 6: 227; Anderson, et al., Handb Exp Pharmacol, 2009, 189: 85).

[0886] 3BP-3407 and 3BP-3554 were tested at 1 μM and 10 μM in duplicates. In the absence of the compound, the fluorescent intensity (Ft) in each data set was defined as 100% activity. In the absence of the enzyme, the background fluorescent intensity (Fb) in each data set was defined as 0% activity. The percent activity in the presence of each compound was calculated according to the following equation: % activity=(F−Fb)/(Ft−Fb), where F=the fluorescent intensity in the presence of the compound. Percentage inhibition was calculated according to the following formula: % inhibition=100%−% activity. Results showing an inhibition higher than 50% are considered to represent significant effects of the tested compound. The results of this assay are given in the following Table 15.

TABLE-US-00015 TABLE 15 Results of the specificity protease screening for 1 μM and 10 μM 3BP-3407 and 1 μM and 10 μM 3BP-3554 Percentage inhibition (%) 3BP-3407 3BP-3554 Enzyme 1 μM 10 μM 1 μM 10 μM Reference Activated 5 8 −11 1 74 Protein C (20 μM Dabigatran) Beta secretase −8 −5 1 7 84 (150 nM Verubecestat) Caspase-3 1 −2 −2 −1 89 (100 nM Caspase 3/7 Inhibitor I) Caspase-6 1 −1 6 −3 94 (1 μM Caspase 8 Inhibitor I) Caspase-7 −3 −3 −1 −7 92 (1 μM Caspase 3/7 Inhibitor I) Caspase-8 0 0 0 −3 87 (100 nM Caspase 8 Inhibitor 1) Caspase-9 5 8 −1 −2 N/A Cathepsin B 26 36 1 2 97 (100 nM E-64) Cathepsin F −3 −24 −23 −25 74 (1 μM Cystatin C) Cathepsin L 3 6 0 −6 97 (1 μM E-64) Cathepsin S 3 18 −10 −23 91 (100 nM E-64) Cathepsin V 1 −18 −1 −1 83 (100 nM E-64) A20 2 −4 1 0 99 (1 μM Ub- Aldehyde) Ataxin3 1 10 2 −1 77 (10 μM Ub- Aldehyde) Deubiquitinase 2 15 0 0 97 OTUD6B (1 μM Ub- Aldehyde) Ubiquitin −2 4 −4 4 92 carboxy-terminal (100 nM Ub- hydrolase L1 Aldehyde) Ubiquitin −1 14 0 0 95 carboxy-terminal (10 nM Ub- hydrolase L3 Aldehyde) Ubiquitin 3 7 0 −1 91 carboxy-terminal (1 μM Ub- hydrolase 2 Aldehyde) Ubiquitin 3 46 −4 −2 84 carboxy-terminal (1 μM Ub- hydrolase 5 Aldehyde) Ubiquitin 5 5 1 1 95 carboxy-terminal (1 μM Ub- hydrolase 7 Aldehyde) Ubiquitin −3 6 2 1 73 carboxy-terminal (1 μM Ub- hydrolase 8 Aldehyde) Ubiquitin −2 5 1 −1 82 carboxy-terminal (1 μM Ub- hydrolase 10 Aldehyde) Ubiquitin −1 5 1 2 96 carboxy-terminal (100 nM Ub- hydrolase 14 Aldehyde) DPP3 ND ND 2 −1 (100 nM Spinorphin) DPP7 2 −3 −1 −7 83 (200 μM KR62436) DPP8 1 5 1 11 96 (200 μM KR62436) DPP9 −1 0 −1 −5 99 (200 μM KR62436) FAP 98 99 97 99 100  (100 nM SP-13786) serine protease 1 −68 −39 −372 94 NS3 (a.a. 3-181) (100 nM from Hepatitis C Denoprevir) virus genotype 1a (mutant D168 V) serine protease 1 5 −5 −9 100  NS3 (a.a. 3-181) (100 nM from Hepatitis C Denoprevir) virus genotype 1b serine protease 1 −6 −2 −17 99 NS3 (a.a. 3-181) (100 nM from Hepatitis C Denoprevir) virus genotype 1b (mutant D168V) serine protease −2 5 −1 0 90 NS3 (a.a. 3-181) (100 nM from Hepatitis C Denoprevir) virus genotype 1b (mutant R155K) serine protease 0 2 0 −5 99 NS3 (a.a. 3-181) (1 μM from Hepatitis C Denoprevir) virus genotype 1b (mutant R155Q) serine protease 0 −2 −13 −40 98 NS3 (a.a. 3-181) (100 nM from Hepatitis C Denoprevir) virus genotype 2a Matrix −1 2 1 −7 87 metalloprotease1 (1 μM NNGH) Matrix 3 3 −1 −2 95 metalloprotease 2 (100 nM NNGH) Matrix 3 2 3 2 92 metalloprotease 9 (100 nM NNGH) (mutant Q279R) Renin −1 3 0 −1 99 (30 nM Aliskiren)

Example 35: .SUP.111.In- and .SUP.177.Lu-Labeling of Selected Compounds

[0887] In order to serve as a diagnostically, therapeutically, or theragnostically active agent, a compound needs to be labeled with a radioactive isotope. The labeling procedure needs to be appropriate to ensure a high radiochemical yield and purity of the radiolabeled compound of the invention. This example shows that the compounds of the present invention are appropriate for radiolabeling and can be labeled in high radiochemical yield and purity.

[0888] 30-100 MBq of .sup.111InCl.sub.3 (in 0.02 M HCl) were mixed with 1 nmol of compound (200 μM stock solution in 0.1 M HEPES pH 7) per 30 MBq and buffer (1 M sodium acetate buffer pH 5 or 1 M sodium acetate/ascorbic acid buffer pH 5 containing 25 mg/ml methionine) at a final buffer concentration of 0.1-0.2 M. The mixture was heated to 80° C. for 20-30 min. After cooling down, DTPA and TWEEN-20 were added at a final concentration of 0.2 mM and 0.1%, respectively.

[0889] 0.2-2.0 GBq .sup.177LuCl.sub.3 (in 0.04 M HCl) were mixed with 1 nmol of compound (200 μM stock solution in 0.1 M HEPES pH 7) per 45 MBq and buffer (1 M sodium acetate/ascorbic acid buffer pH 5 containing 25 mg/ml methionine) at a final buffer concentration of ˜0.4 M. The mixture was heated to 90° C. for 20 min. After cooling down, DTPA and TWEEN-20 were added at a final concentration of 0.2 mM and 0.1%, respectively.

[0890] In order to assess the long-term stability of .sup.177Lu-labeled compound in a formulation suitable for human use, after cooling down the reaction mixture was diluted with 9 volumes of a formulation buffer containing suitable stabilizers (e.g., ascorbate, methionine) and radiochemical purity was monitored over time.

[0891] The labeling efficiency was analyzed by thin layer chromatography (TLC) and HPLC. For TLC analysis, 1-2 μl of diluted labeling solution was applied to a strip of iTLC-SG chromatography paper (Agilent, 7.6×2.3 mm) and developed in citrate-dextrose solution (Sigma). The iTLC strip was then cut into 3 pieces and associated radioactivity was measured with a gamma-counter. The radioactivity measured at the solvent front represents free radionuclide and colloids, whereas the radioactivity at the origin represents radiolabeled compound. For HPLC, 5 μl of diluted labeling solution was analyzed with a Poroshell SB-C18 2.7 μm (Agilent). Eluent A: MeCN, eluent B: H.sub.2O, 0.1% TFA, gradient from 5% B to 70% B within 15 min, flow rate 0.5 ml/min; detector: NaI (Raytest), DAD 230 nm. The peak eluting with the dead volume represents free radionuclide, the peak eluting with the peptide-specific retention time as determined with an unlabeled sample represents radiolabeled compound.

[0892] Radionuclidic incorporation yield was ≥90% and radiochemical purity ≥76% at end of synthesis. Exemplary radiochemical purities for .sup.111In-labeled compounds are shown in Table 16. .sup.177Lu-labeled compounds in formulations suitable for human use maintained a radiochemical purity of >90% up 6 days post synthesis (Table 17). The radiochromatograms for selected compounds are shown in FIGS. 1 to 4, whereby FIG. 1 shows a radiochromatogram of .sup.177Lu-3BP-3407 in formulation buffer containing 100 mg/mL ascorbate and 5 mg/mL L-methionine analyzed immediately after synthesis, FIG. 2 shows a radiochromatogram of .sup.177Lu-3BP-3407 in formulation buffer containing 100 mg/mL ascorbate and 5 mg/mL L-methionine analyzed six days after synthesis, FIG. 3 shows a radiochromatogram of .sup.177Lu-3BP-3554 in formulation buffer containing 100 mg/mL ascorbate and 5 mg/mL L-methionine analyzed immediately after synthesis, and FIG. 4 shows a radiochromatogram of .sup.177Lu-3BP-3554 in formulation buffer containing 100 mg/mL ascorbate and 5 mg/mL L-methionine analyzed six days after synthesis.

TABLE-US-00016 TABLE 16 Radiochemical purity by HPLC of 111In-labeled compounds. HPLC HPLC Area % HPLC Area % retention time at end of appr. 4 h post [min] synthesis end of synthesis .sup.111In -3BP-3105 8.9 92.9 86.0 .sup.111In -3BP-3168 7.9 94.2 92.3 .sup.111In -3BP-3275 8.6 91.5 91.2 .sup.111In -3BP-3320 7.4 97.7 96.5 .sup.111In -3BP-3321 7.3 97.6 96.7 .sup.111In -3BP-3397 8.3 76.3 77.6 .sup.111In-3BP-3398 7.3 88.6 89.2 .sup.111In-3BP-3407 7.3 97.6 95.4 .sup.111In-3BP-3554 7.5 95.6 96.2 .sup.111In-3BP-3652 7.3 87.1 88.8 .sup.111In-3BP-3654 7.8 88.2 86.4 .sup.111In-3BP-3656 7.3 87.8 87.1 .sup.111In-3BP-3659 7.3 94.5 95.6 .sup.111In-3BP-3678 7.4 89.9 89.2 .sup.111In-3BP-3692 7.8 93.0 93.3 .sup.111In-3BP-3767 7.4 94.6 92.9

TABLE-US-00017 TABLE 17 Radiochemical purity by HPLC of .sup.177Lu-labeled compounds in a formulation buffer containing 100 mg/mL ascorbate and 5 mg/mL L-methionine analyzed on day 0 and day 6 post end of synthesis. HPLC retention HPLC Area % HPLC Area % time [min] Day 0 Day 6 .sup.177Lu-3BP-3407 7.5 95.7 94.0 .sup.177Lu-3BP-3554 7.6 97.2 95.6

Example 36: Imaging and Biodistribution Studies

[0893] Radioactively labeled compounds can be detected by imaging methods such as SPECT and PET. Furthermore, the data acquired by such techniques can be confirmed by direct measurement of radioactivity contained in the individual organs prepared from an animal injected with a radioactively labeled compound of the invention. Thus, the biodistribution (the measurement of radioactivity in individual organs) of a radioactively labeled compound can be determined and analyzed. This example shows that the compounds of the present invention show a biodistribution appropriate for diagnostic imaging and therapeutic treatment of tumors.

[0894] All animal experiments were conducted in compliance with the German animal protection laws. Male SCID beige (6- to 8-week-old, Charles River, Sulzfeld, Germany) were inoculated with 5×10.sup.6 HEK-FAP (embryonic human kidney 293 cells genetically engineered to express high levels of FAP) cells in one shoulder. When tumors reached a size of >150 mm.sup.3 mice received ˜30 MBq .sup.111In-labelled compounds of the invention (diluted to 100 μL with PBS) administered intravenously via the tail vein. Images were obtained on a NanoSPECT/CT system (Mediso Medical Imaging Systems, Budapest, Hungary) using exemplarily the following acquisition and reconstruction parameters (Table 18).

TABLE-US-00018 TABLE 18 Acquisition and reconstruction parameters of NanoSPECT/CT imaging Acquistion parameters SPECT System NanoSPECT/CT ™ Scan range whole body, 3-bed holder (mouse hotel) Time per projection 60 s Aperture model, pinhole Aperture #2, 1.5 mm diameter Reconstruction parameters Method HiSPECT (Scivis), iterative reconstruction Smoothing 35% Iterations 9 Voxel size 0.15 mm × 0.15 mm × 0.15 mm Acquisition parameters CT System NanoSPECT/CT ™ Scan range whole body, 3-bed holder (mouse hotel) Scan duration 7 minutes Tube voltage 45 kVp Exposure time 500 ms Number of projections 240

[0895] Imaging data were saved as DICOM files and analysed using VivoQuant™ software (Invicro, Boston, USA). Results are expressed as a percentage of injected dose per gram of tissue (% ID/g). For biodistribution studies, animals were sacrificed by cervical dislocation at 24 h or 48 h post injection and then dissected. Different organs and tissues were collected and weighed, and the radioactivity was determined by γ-counting. Two animals were used per time point. Results are expressed as a percentage of injected dose per gram of tissue (% ID/g).

[0896] The results of the imaging and biodistribution studies for selected compounds are shown in FIGS. 5-14.

Example 37: Efficacy Study—HEK-FAP

[0897] Radioactively labeled compounds can be used for therapeutic and diagnostic application in various diseases, especially cancer. This example shows that the compounds of the present invention have anti-tumor activity suitable for the therapeutic treatment of tumors.

[0898] All animal experiments were conducted in compliance with the German animal protection laws. Female swiss nude mice (7- to 8-week-old, Charles River Laboratories, France) were inoculated with 5×10.sup.6 HEK-FAP cells in one shoulder, and treatments were administered when the tumors reached a mean tumor volume of 160±44 mm.sup.3. Mice were divided into 4 different groups of 10 animals/group: Group 1—vehicle control, Group 2—cold compound .sup.177Lu-3BP-3554, Group 3-30 MBq .sup.177Lu-3BP-3554 (low dose), and Group 4-60 MBq .sup.177Lu-FAP-3554 (high dose). Treatments were administered on Day 0 by intravenous injection into the tail vein at 4 mL/kg (100 μL/mouse). Tumor volume and body weights were measured at Day 0 (i.e. the first day of radiotracer administration) and then thrice weekly until completion of the study.

[0899] The tracer distribution in mice injected with .sup.177Lu-labeled 3BP-3554 was determined by SPECT imaging in three mice dosing group. Subsequently, following SPECT, a CT scan was done for anatomical information. Imaging was performed 3 h, 24 h, 48 h and 120 h post injection with a NanoSPECT/CT system (Mediso Medical Imaging Systems, Budapest, Hungary) using exemplarily the following acquisition and reconstruction parameters (Table 19).

TABLE-US-00019 TABLE 19 Acquisition and reconstruction parameters of NanoSPECT/CT imaging Acquistion parameters SPECT System NanoSPECT/CT  ™ Scan range whole body, 3-bed holder (mouse hotel) Time per projection 60 s or 120 s Aperture model, pinhole Aperture #2, 1.5 mm diameter Reconstruction parameters Method HiSPECT (Scivis), iterative reconstruction Smoothing 35% Iterations 9 Voxel size 0.15 mm × 0.15 mm × 0.15 mm Acquisition parameters CT System NanoSPECT/CT ™ Scan range whole body, 3-bed holder (mouse hotel) Scan duration 7 minutes Tube voltage 45 kVp Exposure time 500 ms Number of projections 240

[0900] Imaging data were saved as DICOM files and analysed using VivoQuant™ software (Invicro, Boston, USA). Results are expressed as a percentage of injected dose per gram of tissue (% ID/g).

[0901] Tumors in vehicle and cold compound .sup.natLu-3BP-3554-treated mice reached a mean tumor volume (MTV) of 1338±670 mm.sup.3 and 1392±420 mm.sup.3 on day 14, respectively (FIG. 15 A). Statistically significant (P<0.01) anti-tumor activity was observed in mice of both treatment groups. Tumor growth inhibition (TGI) at day 14 was 111% and 113% in mice treated with a single dose of 30 or 60 MBq .sup.177Lu-3BP-3554, respectively, relative to the vehicle-treated group. The MTV in all mice treated with .sup.177Lu-3BP-3554 was reduced to ≤70 mm.sup.3 on day 14. Tumors were monitored for regrowth on day 42 (which represents the end of the study) three of ten and nine of ten mice treated with 30 or 60 MBq .sup.177Lu-3BP-3554, respectively, were tumor-free (<10 mm.sup.3), suggesting a potential dose-response in this model. No treatment-related body weight loss was observed throughout the study (FIG. 15 B). After a 3-5% decrease in body weight observed in all groups on Day 2, the body weight of the animals increased over time.

[0902] SPECT/CT imaging of 3 animals of both .sup.177Lu-labeled treatment groups showed high tumor-to-background contrast during all examined time points (3-120 h post-injection (p.i.)). High tumor retention up to 120 h was observed. The organ with the highest non-target uptake was the kidney, with tumor-to-kidney ratios of 8.6±0.6 and 8.0±1.6 at 3 h p.i. in mice treated with 30 or 60 MBq .sup.177Lu-3BP3554, respectively. These ratios increased over time, attaining the highest value at 120 h with 40±7.9 and 32±7.4 tumor-to-kidney ratios in mice treated with 30 or 60 MBq .sup.177Lu-3BP3554, respectively. An exemplary panel of SPECT/CT images for mouse 5 which was a high dose animal is shown in FIG. 16 A and for mouse 1 which was a low-dose animal is shown in FIG. 16 B.

Example 38: Imaging Study—Sarcoma PDX Models

[0903] Sarcoma tumors have been reported to express FAP, and imaging of four different sarcoma patient-derived xenograft (PDX) tumor models was performed to evaluate 3BP-3554 uptake. The Sarc4183, Sarc4605, Sarc4809 and Sarc12616 PDX models were derived from patients with rhabdomyosarcoma, osteosarcoma, undifferentiated sarcoma and undifferentiated pleiomorphic sarcoma, respectively (Experimental Pharmacology & Oncology Berlin-Buch, Germany). Tumor fragments were transplanted subcutaneously in the left flank of 8-week-old NMRI nu/nu mice (Janvier Labs, France). All animal experiments were conducted in compliance with the German animal protection laws. 47 days (Sarc4183, Sarc4809) or 46 days (Sarc4605, Sarc12616) after transplantation, 2-3 mice per model were imaged 3 hours after a single intravenous injection of 30 MBq of .sup.111In-3BP-3554. Imaging was performed as described in Example 36.

[0904] The imaging results with .sup.111In-3BP-3554 showed high tumor uptake 3 h p.i. and a high tumor-to-background contrast. Representative SPECT/CT images are shown in FIG. 17 A. Quantification of tumor uptake of two (Sarc4605, Sarc12616) or three (Sarc4183, Sarc4809) PDX-bearing mice, respectively, revealed % ID/g values of 4.9±1.7 (Sarc4183), 5.2±0.8 (Sarc4605), 4.4±0.7 (Sarc4809) and 6.1±0.6 (Sarc12616) as shown in FIG. 17 B. These results demonstrate .sup.111In-3BP-3554 uptake in all 4 sarcoma models. Tumor-to-kidney ratios were 4.7±1.2 (Sarc4183), 3.2±0.4 (Sarc4605) 4.1±0.7 (Sarc4809) and 4.3±1.2 (Sarc12616).

Example 39: Efficacy Study—Sarcoma Sarc4809 PDX Model

[0905] The efficacy of .sup.177Lu-3BP-3554 was investigated in the human sarcoma PDX tumor model Sarc4809. This model of an undifferentiated sarcoma demonstrates .sup.111In-3BP-3554 uptake (Example 38) and was also shown to express FAP by immunohistochemistry.

[0906] All animal experiments were conducted in compliance with the German animal protection laws. Sarc4809 tumor fragments were transplanted subcutaneously at the left flank of 8-week-old NMRI nu/nu mice (Janvier Labs, France). Treatment started 23 days after transplantation at a mean tumor volume of 187.08±123.8 mm.sup.3. Mice were split into four groups of 10 animals/group: Group 1—vehicle control, Group 2—cold compound .sup.natLu-FAP-3554, Group 3—30 MBq .sup.177Lu-3BP-3554, Group 4-60 MBq .sup.177Lu-FAP-3554. Treatments were administered on Day 0 by intravenous injection into the tail vein at 4 mL/kg (100 μL/mouse). Tumor volume and body weight were determined at Day 0 (i.e. the first day of radiotracer administration) and then thrice weekly until completion of the study.

[0907] All tumors continuously grew throughout the follow-up period of the study until day 42. Tumors in vehicle and .sup.natLu-3BP-3554 treated mice (control groups) reached an MTV of 894±610 mm.sup.3 and 1225±775 mm.sup.3 on day 31 (the last day on which at least 50% mice per group were still alive), respectively. Tumors in mice treated with a single dose of 30 or 60 MBq .sup.177Lu-3BP-3554 reached an MTV of 635±462 and 723±391 mm.sup.3 on day 31, respectively (FIG. 18A). Statistically significant (P<0.05) anti-tumor activity was observed in mice of both treatment groups. Tumor growth inhibition (TGI) at day 31 was 61% and 73% in mice treated with a single dose of 30 or 60 MBq .sup.177Lu-3BP-3554, respectively, relative to the vehicle-treated group. No treatment-related body weight loss (BWL) was observed throughout the study. In all groups body weight increased during study follow-up (FIG. 18B).

Example 40: Pharmacokinetic Studies

[0908] The pharmacokinetic behavior of selected compounds was assessed in mice and rats. This characterization of the pharmacokinetic behavior of a compound enables new insights into distribution and elimination of the compound and the calculation of the exposure.

[0909] Different amounts of the compounds were stable formulated in PBS. The formulations were applied intravenous with a dose of 4 nmol/kg, 40 nmol/kg and 400 nmol/kg in mice and 2 nmo/kg, 20 nmol/kg and 200 nmol/kg (3BP-3554) or 40 nmol/kg and 400 mol/kg (3BP-3623) in rats. Assuming an allometric translation factor of 12.3 from human to mouse, and 6.2 from human to rats (Nair A B, Jacob S. Journal of Basic and Clinical Pharmacy, 2016, 7(2): 27-31), the applied doses represent a human dose range of 0.325 nmol/kg to 32.5 nmol/kg.

[0910] Blood samples were collected after different times (5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h) from tail vein (rats) or retrobulbar (mice).

[0911] After separation of the blood cells from the blood plasma by centrifugation, the compounds were quantified in the prepared plasma samples were subjected to a protein precipitation procedure. 150 μl of a zinc sulphate precipitation agent containing 78% 0.1 M zinc sulphate and 22% acetonitrile was added. After incubation at room temperature for 30 min the precipitate was separated by centrifugation. To 100 μl of the supernatant 10 μl of 1% formic acid was added followed by further incubation at 60° C. for 10 min to complete the formation of the zinc chelate, if the compound contains a free DOTA moiety.

[0912] The determination of the analyte in the clean sample solutions was performed on an Agilent 1290 UHPLC system coupled to an Agilent 6470 triple quadrupole mass spectrometer. The chromatographic separation was carried out on a Phenomenex BioZen Peptide XB-C18 HPLC column (50×2 mm, 1.7 μm particle size) at 40° C. with gradient elution using a mixture of0.1% formic acid in water as eluent A and acetonitrile as eluent B (isocratic at 5% B for 1 min followed by a linear gradient to 43% B in 4 min, 500 μl/min).

[0913] Mass spectrometric detection was performed in positive ion ESI mode by multiple reaction monitoring (MRM) with detection parameters as described in Table 20.

TABLE-US-00020 TABLE 20 Mass spectrometric detection parameters Collision Compound Fragmentor Precursor Product energy 3BP-4343 190 V Quantifier 767.0 683.2 24 V Qualifier 767.0 542.9 38 V 3BP-3623 110 V Quantifier 791.8 777.6 21 V Qualifier 791.8 708.2 19 V

[0914] Quantitation of test items was accomplished using the Quantitative Analysis software of the Agilent MassHunter software suite. A quadratic regression was performed with a weighting factor of 1/x.

[0915] The plasma level were subjected to a non-compartmental analysis (NCA) with following results: initial concentration of the compound (C.sub.0), volume of distribution at steady state (V.sub.ss), volume of distribution in the terminal phase (V.sub.z), terminal half-life (t.sub.1/2), clearance (CL) and area under the curve extrapolated to infinity (AUC.sub.inf). A summary of NCA parameters of 3BP-3554 are presented in Table 21 for 3BP-3554 in mouse plasma and in Table 22 for 3BP-3554 in rat plasma, and of NCA parameters of 3BP-3623 in Table 23 for 3BP-3623 in mouse plasma and in Table 24 for 3BP-3623 in rat plasma.

TABLE-US-00021 TABLE 21 Summary of NCA parameters of 3BP-3554 in mouse plasma PK parameter 4 nmol/kg 40 nmol/kg 400 nmol/kg C.sub.0 25.6 nM 177 nM 4970 nM V.sub.ss 0.21 L/kg 0.32 L/kg 0.10 L/kg V.sub.z 0.26 L/kg 1.02 L/kg 0.21 L/kg AUC.sub.inf 8.3 nM h 56 nM h 961 nM h t.sub.1/2 23 min 59 min 40 min CL 0.482 L/kg h 0.711 L/kg 0.482 L/kg h

TABLE-US-00022 TABLE 22 Summary of NCA parameters of 3BP-3554 in rat plasma PK parameter 2 nmol/kg 20 nmol/kg 200 nmol/kg C.sub.0 10.3 nM 111 nM 1480 nM V.sub.ss 0.28 L/kg 0.30 L/kg 0.17 L/kg V.sub.z 0.32 L/kg 0.35 L/kg 0.42 L/kg AUC.sub.inf 8.1 nM h 69 nM h 726 nM h t.sub.1/2 54 min 50 min 63 min CL 0.248 L/kg h 0.291 L/kg h 0.275 L/kg h

TABLE-US-00023 TABLE 23 Summary of NCA parameters of 3BP-3623 in mouse plasma PK parameter 4 nmol/kg 40 nmol/kg 400 nmol/kg C.sub.0 17.6 nM 228 nM 2134 nM V.sub.ss 0.36 L/kg 0.31 L/kg 0.20 L/kg V.sub.z 0.44 L/kg 0.53 L/kg 0.64 L/kg AUC.sub.inf 7.7 nM h 55 nM h 532 nM h t.sub.1/2 35 min 30 min 35 min CL 0.518 L/kg h 0.722 L/kg h 0.752 L/kg h

TABLE-US-00024 TABLE 24 Summary of NCA parameters of 3BP-3623 in rat plasma PK parameter 40 nmol/kg 400 nmol/kg C.sub.0 127 nM 1408 nM V.sub.ss 0.48 L/kg 0.32 L/kg V.sub.z 0.58 L/kg 0.93 L/kg AUC.sub.inf 74 nM h 738 nM h t.sub.1/2 45 min 71 min CL 0.541 L/kg h 0.542 L/kg h

[0916] The results indicate distribution mainly in the blood and interstitial fluids and a clearance typical for peptides with terminal half-lifes between 23 min and 59 min in mice and between 45 min and 71 min in rats. Exposure as described by the AUC correlates almost linear to the injected dose and the clearance is constant for all applied doses in a particular animal model. These observations suggest no significant non-linearity of the pharmacokinetic behavior that need to be considered for first-in-human dose calculation.

[0917] The features of the present invention disclosed in the specification, the claims, the sequence listing and/or the drawings may both separately and in any combination thereof be material for realizing the invention in various forms thereof.

REFERENCES

[0918] The disclosure of each and any document recited herein is incorporated by reference.