RADIOLABELED COMPOUNDS TARGETING THE PROSTATE-SPECIFIC MEMBRANE ANTIGEN

Abstract

A compound comprising a prostate specific membrane antigen (PSMA)-targeting moiety of the following formula (I) or of a salt or a solvate thereof. R.sup.1 is R.sup.1aR.sup.1b wherein R.sup.1a is absent, CH.sub.2, O, or S, and R.sup.1b is CH.sub.2 or CHF. R.sup.2 is (CH.sub.2).sub.3O, (CH.sub.2).sub.3, (CH.sub.2).sub.4, CH.sub.2O(CH.sub.2).sub.2, or CH.sub.2S(CH.sub.2).sub.2. R.sup.3 is ethylene fused to a tricyclic fused ring. L.sup.1, L.sup.2, L.sup.3, L.sup.4, L.sup.5b L.sup.5c, L.sup.6 and L.sup.7 are linkages (e.g. peptide bonds). X.sup.br is a branching atom. R.sup.rad is a radiometal chelator. R.sup.alb is an albumin binder. n1, n2, n3, n4, and n5 are integers. When the PSMA-targeting moiety is linked to a radiolabeling group, the compound may be used as an imaging agent or therapeutic agent for PSMA-expressing diseases/conditions.

##STR00001##

Claims

1. A compound, wherein the compound has Formula I or is a salt or a solvate of Formula I: ##STR00117## wherein: R.sup.1 is R.sup.1aR.sup.1b, wherein R.sup.1a is absent, CH.sub.2, O, or S, and R.sup.1b is CH.sub.2 or CHF; R.sup.2 is (CH.sub.2).sub.3O, (CH.sub.2).sub.3, (CH.sub.2).sub.4, CH.sub.2O(CH.sub.2).sub.2, or CH.sub.2S(CH.sub.2).sub.2; L.sup.1 is S, N(R.sup.L1a)C(O), C(O)N(R.sup.L1a), NHC(O)NH, NHC(S)NH, ##STR00118## wherein R.sup.L1a is H, methyl, ethyl or a benzyl group with 0-4 substituents independently selected from halogen, OMe, or SMe; R.sup.3 is: ##STR00119## substituted with 0-4 substituents independently selected from C.sub.1-C.sub.4 alkyl, halogen, OMe, SMe, NH.sub.2, NO.sub.2, CN, or OH, and wherein 0-4 ring carbons are replaced with nitrogen; L.sup.2 is S, N(R.sup.L2a)C(O), C(O)N(R.sup.L2a), NHC(O)NH, NHC(S)NH, ##STR00120## wherein R.sup.L2a is H, methyl, or ethyl; each of n1 and n2 is 0-2; ring A has 0-3 double bonds, and is bonded at meta or para position; each of L.sup.3, L.sup.4, L.sup.5b, L.sup.5c, L.sup.6, and L.sup.7 is independently S, N(R.sup.L3a)C(O), C(O)N(R.sup.L3a), NHC(O)NH, NHC(S)NH, ##STR00121## wherein each R.sup.L3a is independently H, methyl, or ethyl; each of n3, n4, and n5 is independently 0-4; each R.sup.4 is independently a linear, branched, and/or cyclic C.sub.n6 alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n6 is independently 1-20, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid; and R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a linear, branched, and/or cyclic C.sub.n7 alkylenyl, alkenylenyl and/or alkynylenyl, wherein n7 is 1-20, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, wherein carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid, wherein one, two, or three of R.sup.5a, R.sup.5b, and R.sup.5c are optionally absent, wherein X.sup.br is CH or N and wherein X.sup.br is separated from ring A by at least 4 atoms; each R.sup.6 and each R.sup.7 is independently a linear, branched, and/or cyclic C.sub.n8 alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n8 is independently 1-20, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid; R.sup.rad is a radiometal chelator, optionally bound by a radiometal, wherein R.sup.rad is separated from ring A by at least 7 atoms; and R.sup.alb is an albumin binder, wherein the albumin binder is: (CH.sub.2).sub.n9CH.sub.3 wherein n9 is 8-20; (CH.sub.2).sub.n10C(O)OH wherein n10 is 8-20; or ##STR00122## wherein n11 is 1-4 and R.sup.8 is I, Br, F, Cl, H, OH, OCH.sub.3, NH.sub.2, NO.sub.2, or CH.sub.3; and R.sup.alb is separated from ring A by at least 7 atoms.

2. The compound of claim 1, wherein R.sup.alb is separated from ring A by 7-18 atoms, and R.sup.rad is separated from ring A by 7-18 atoms.

3. The compound of claim 1 or 2, wherein R.sup.1a is CH.sub.2, O, or S, optionally wherein R.sup.1 is (CH.sub.2).sub.2.

4. The compound of any one of claims 1 to 3, wherein R.sup.alb is ##STR00123## wherein n11 is 1-4 and R.sup.8 is OCH.sub.3 or NO.sub.2.

5. The compound of claim 4, wherein n11 is 3.

6. The compound of any one of claims 1 to 5, wherein R.sup.2 is (CH.sub.2).sub.4.

7. The compound of any one of claims 1 to 6, wherein L.sup.1 is N(R.sup.L1a)C(O) or C(O)N(R.sup.L1a) wherein L.sup.1a is H or methyl, optionally wherein L.sup.1 is NHC(O).

8. The compound of any one of claims 1 to 7, wherein R.sup.3 is: ##STR00124##

9. The compound of any one of claims 1 to 8, wherein L.sup.2 is N(R.sup.L2a)C(O) or C(O)N(R.sup.L2a), wherein R.sup.L2a is H or methyl, optionally wherein L.sup.2 is NHC(O).

10. The compound of any one of claims 1 to 9, wherein n1 is 0.

11. The compound of any one of claims 1 to 10, wherein ring A has 0 double bonds and is bonded at para position.

12. The compound of claim 11, wherein ring A is ##STR00125##

13. The compound of any one of claims 1 to 12, wherein n2 is 0 or 1.

14. The compound of any one of claims 1 to 13, wherein each L.sup.3 is independently N(R.sup.L3a), C(O) or C(O)N(R.sup.L3a) wherein each R.sup.L3a is independently H or methyl, optionally wherein each L.sup.3 is NHC(O).

15. The compound of any one of claims 1 to 14, wherein each L.sup.4 is independently N(R.sup.L4a), C(O) or C(O)N(R.sup.L4a) wherein each R.sup.L4a is independently H or methyl, optionally wherein each L.sup.4 is NHC(O).

16. The compound of any one of claims 1 to 15, wherein R.sup.4 is methylene.

17. The compound of any one of claims 1 to 16, wherein n3 is 1.

18. The compound of any one of claims 1 to 17, wherein R.sup.5a is absent.

19. The compound of any one of claims 1 to 13, wherein the compound has Formula II or is a salt or a solvate of Formula II: ##STR00126##

20. The compound of any one of claims 1 to 19, wherein X.sup.br is CH.

21. The compound of any one of claims 1 to 20, wherein R.sup.5b is absent or (CH.sub.2).sub.1-4.

22. The compound of any one of claims 1 to 21, wherein R.sup.5c is absent or (CH.sub.2).sub.1-4.

23. The compound of any one of claims 1 to 22, wherein L.sup.5b is N(R.sup.L5b)C(O) or C(O)N(R.sup.L5b) wherein R.sup.L5b is H or methyl, optionally wherein L.sup.5b is NHC(O).

24. The compound of any one of claims 1 to 23, wherein L.sup.5c is N(R.sup.L5c)C(O) or (O)N(R.sup.L5c) wherein R.sup.L5c is H or methyl, optionally wherein L.sup.5c is NHC(O).

25. The compound of any one of claims 1 to 24, wherein each R.sup.6 is (CH.sub.2).sub.1-4.

26. The compound of any one of claims 1 to 25, wherein each L.sup.6 is independently N(R.sup.L6a), C(O) or C(O)N(R.sup.L6a) wherein each R.sup.L6a is independently H or methyl, optionally wherein each L.sup.6 is NHC(O).

27. The compound of any one of claims 1 to 26, wherein n4 is 0 or 1.

28. The compound of any one of claims 1 to 27, wherein each R.sup.7 is (CH.sub.2).sub.1-4.

29. The compound of any one of claims 1 to 28, wherein each L.sup.7 is independently N(R.sup.L7a), C(O) or C(O)N(R.sup.L7a) wherein each R.sup.L7a is independently H or methyl, optionally wherein each L.sup.7 is NHC(O).

30. The compound of any one of claims 1 to 29, wherein n5 is 0 or 1.

31. The compound of any one of claims 1 to 30, wherein X.sup.br is separated from ring A by at least 5 atoms, optionally at least 6 atoms.

32. The compound of claim 1 or claim 19, wherein: R.sup.1 is R.sup.1aR.sup.1b, wherein R.sup.1a is absent or CH.sub.2, and R.sup.1b is CH.sub.2 or CHF; R.sup.2 is (CH.sub.2).sub.3O, (CH.sub.2).sub.3, (CH.sub.2).sub.4, or CH.sub.2O(CH.sub.2).sub.2; L.sup.1 is N(R.sup.L1a)C(O), C(O)N(R.sup.L1a), or NHC(O)NH, wherein R.sup.L1a is H or methyl; R.sup.3 is: ##STR00127## L.sup.2 is N(R.sup.L2a)C(O), C(O)N(R.sup.L2a), NHC(O)NH, wherein R.sup.L2a is H, or methyl; each of n1 and n2 is 0-2; ring A has 0 double bond, and is bonded at meta or para position; each of L.sup.3, L.sup.4, L.sup.5b, L.sup.5c, L.sup.6, and L.sup.7 is independently N(R.sup.L3a)C(O), C(O)N(R.sup.L3a), or NHC(O)NH, wherein each R.sup.L3a is independently H, methyl, or ethyl; each of n3, n4, and n5 is independently 0-4; each R.sup.4 is independently a linear C.sub.1-C.sub.10 alkylenyl; R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a linear, branched, and/or cyclic C.sub.1-C.sub.20 alkylenyl, alkenylenyl and/or alkynylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, wherein carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid, wherein one, two, or three of R.sup.5a, R.sup.5b, and R.sup.5c are optionally absent, wherein X.sup.br is N or CH, and wherein X.sup.br is separated from ring A by at least 4 atoms; each R.sup.6 and each R.sup.7 is independently a linear, branched, and/or cyclic C.sub.1-C.sub.20 alkylenyl, alkenylenyl and/or alkynylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid; R.sup.rad is a radiometal chelator, optionally bound by a radiometal, wherein R.sup.rad is separated from ring A by at least 7 atoms; and R.sup.alb is: ##STR00128## wherein n11 is 1-4 and R.sup.8 is I, Br, F, Cl, H, OH, OCH.sub.3, NH.sub.2, NO.sub.2, or CH.sub.3.

33. The compound of claim 32, wherein: R.sup.2 is (CH.sub.2).sub.3, or (CH.sub.2).sub.4; L.sup.1 is N(R.sup.L1a)C(O), or C(O)N(R.sup.L1a), wherein R.sup.L1a is H or methyl; R.sup.3 is: ##STR00129## L.sup.2 is N(R.sup.L2a)C(O), or C(O)N(R.sup.L2a), wherein R.sup.L2a is H, or methyl; each of n1 and n2 is 0-1; each of L.sup.3, L.sup.4, L.sup.5b, L.sup.5c, L.sup.6, and L.sup.7 is independently N(R.sup.L3a)C(O), or C(O)N(R.sup.L3a), wherein each R.sup.L3a is independently H or methyl; each R.sup.4 is independently a linear C.sub.1-C.sub.10 alkylenyl; R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a linear, branched, and/or cyclic C.sub.1-C.sub.10 alkylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by O, wherein carbons are optionally independently substituted with oxo, hydroxyl, amine, amide, or carboxylic acid, wherein one, two, or three of R.sup.5a, R.sup.5b, and R.sup.5c are optionally absent, wherein X.sup.br is N or CH and wherein X.sup.br is separated from ring A by at least 4 atoms; each R.sup.6 and each R.sup.7 is independently a linear, branched, and/or cyclic C.sub.1-C.sub.10 alkylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, amine, amide, urea, carboxylic acid; and R.sup.alb is: ##STR00130## wherein n11 is 1-4 and R.sup.8 is OCH.sub.3, or NO.sub.2.

34. The compound of claim 32 or 33, wherein L.sup.3 is NHC(O).

35. The compound of any one of claims 32-34, wherein L.sup.4 is NHC(O).

36. The compound of any one of claims 32-35, wherein R.sup.4 is methylene.

37. The compound of any one of claims 32-36, wherein n3 is 1-4.

38. The compound of claim 37, wherein n3 is 1-2.

39. The compound of claim 37, wherein n3 is 1.

40. The compound of any one of claims 32-39, wherein n2 is 0-1.

41. The compound of claim 40, wherein n2 is 1.

42. The compound of any one of claims 32-41, wherein R.sup.5a is absent.

43. The compound of any one of claims 32-41, wherein R.sup.5a is methylene.

44. The compound of any one of claims 1, 19, 32 or 33, wherein ring A is ##STR00131## R.sup.2 is (CH.sub.2).sub.4; R.sup.3 is: ##STR00132## n1 is 0; L.sup.1 is N(R.sup.L1a)C(O), or C(O)N(R.sup.L1a), wherein R.sup.L1a is H; L.sup.2 is N(R.sup.L2a)C(O), or C(O)N(R.sup.L2a), wherein R.sup.L2a is H; and R.sup.1 is R.sup.1aR.sup.1b, wherein R.sup.1a is CH.sub.2, and R.sup.1b is CH.sub.2 or CHF.

45. The compound of claim 44, wherein R.sup.5c is absent; L.sup.5c is N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; R.sup.7 is methylene; L.sup.7 is N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; n5 is 1; and R.sup.alb is: ##STR00133## wherein n11 is 3 and R.sup.8 is OCH.sub.3, or NO.sub.2.

46. The compound of claim 44 or 45, wherein n2 is 0 or 1; L.sup.3 is N(R.sup.L3a)C(O), or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; R.sup.4 is methylene; L.sup.4 is N(R.sup.L3a)C(O), or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; n3 is 1; R.sup.5a is absent; and X.sup.br is CH;

47. The compound of any one of claims 44-46, wherein R.sup.5b is a linear C.sub.1-C.sub.6 alkylenyl; L.sup.5b is N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; R.sup.6 is methylene; L.sup.6 is N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; and n4 is 0-2.

48. The compound of any one of claims 1-47, wherein R.sup.rad is selected from Table 2; and wherein R.sup.rad is optionally bound to a radiometal.

49. The compound of any one of claims 1-48, wherein R.sup.rad is DOTA, H.sub.2macropa, H.sub.4 py4 pa, H.sub.4Pypa, or CROWN, wherein R.sup.rad is optionally bound to a radiometal.

50. The compound of claim 49, wherein R.sup.rad is DOTA.

51. The compound of any one of claims 1 to 50, wherein R.sup.rad is bound by a therapeutic radiometal, optionally wherein the therapeutic radiometal is .sup.165Er, .sup.212Bi, .sup.166Ho, .sup.149Pm, .sup.159Gd, .sup.105Rh, .sup.109Pd, .sup.198Au, .sup.199Au, .sup.175Yb, .sup.142Pr, .sup.177Lu, .sup.111In, .sup.213Bi, .sup.212Pb, .sup.47Sc, .sup.90Y, .sup.225Ac, .sup.117mSn, .sup.153Sm, .sup.149Tb, .sup.161Tb, .sup.224Ra, .sup.227Th, .sup.223Ra, .sup.64Cu, or .sup.67Cu.

52. A compound selected from CCZ02009, CCZ02017, CCZ02008, CCZ02025, CCZ02024, CCZ02015, CCZ02019, CCZ02012, CCZ02005, CCZ02021, CCZ02022, CCZ02059, CCZ02060, CCZ02034, CCZ02061, or CCZ02013, wherein the compound is optionally bound to a radiometal.

53. A compound selected from CCZ02005, CCZ02021, CCZ02022, CCZ02059, CCZ02060, CCZ02034, CCZ02061, wherein the compound is optionally bound to a radiometal.

54. A compound selected from CCZ02009, CCZ02017, CCZ02008, CCZ02025, CCZ02024, CCZ02015, or CCZ02019, wherein the compound is optionally bound to a radiometal.

55. The compound of any one of claims 1-54, wherein the radiometal is .sup.165Er, .sup.212Bi, .sup.166Ho, .sup.149Pm, .sup.159Gd, .sup.105Rh, .sup.109Pd, .sup.198Au, .sup.199Au, .sup.175Yb, .sup.142Pr, .sup.177Lu, .sup.111In, .sup.213Bi, .sup.212Pb, .sup.47Sc, .sup.90Y, .sup.225Ac, .sup.117mSn, .sup.153Sm, .sup.149Tb, .sup.161Tb, .sup.224Ra, .sup.227Th, .sup.223Ra, .sup.64Cu, or .sup.67Cu.

56. The compound of claim 55, wherein the radiometal is .sup.177Lu or .sup.225Ac.

57. A pharmaceutical composition comprising a compound of any one of claims 1-56 and one or more pharmaceutically acceptable excipients.

58. The compound of any one of claims 1-56 or the pharmaceutical composition of claim 57, for use in treatment of a prostate-specific membrane antigen (PSMA) expressing tumor in a subject.

59. The compound of claim 58, wherein the prostate-specific membrane antigen (PSMA) expressing tumor relates to prostate cancer.

60. The compound of claim 58 or 59, wherein the subject is human.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The features of the invention will become apparent from the following description in which reference is made to the appended drawings wherein:

[0009] FIG. 1 shows examples of prior art PSMA-targeting compounds for prostate cancer imaging.

[0010] FIG. 2A shows representative in vitro competitive PSMA binding assay curves using LNCaP cells with CCZ02009 (left panel) and HTK03170 (right panel). FIG. 2B shows PET images of .sup.68Ga-CCZ02009 in NRG-mice bearing LNCaP tumors at 1 (left panel) and 3 h p.i. (right panel).

[0011] FIG. 3 shows representative in vitro competitive PSMA binding assay curves using LNCaP cells with CCZ02060 (left panel) and CCZ02059 (right panel).

[0012] FIG. 4 shows SPECT/CT images of .sup.177Lu-CCZ02017 in NRG-mice bearing LNCaP tumors at 3, 24, 72, 144 and 240 h p.i.

[0013] FIG. 5 shows a representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02008.

[0014] FIG. 6 shows a representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02025.

[0015] FIG. 7 shows a representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02024.

[0016] FIG. 8 shows a representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02015.

[0017] FIGS. 9A-9B show representative in vitro competitive PSMA binding assay curves using LNCaP cells with CCZ02012 (FIG. 9A) and CCZ02013 (FIG. 9B).

[0018] FIGS. 10A-10B show representative in vitro competitive PSMA binding assay curves using LNCaP cells with CCZ02021 (FIG. 10A) and CCZ02022 (FIG. 10B).

[0019] FIG. 11 shows a representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02034.

[0020] FIG. 12 shows a representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02005.

[0021] FIG. 13 shows a representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02061.

DETAILED DESCRIPTION

[0022] All publications, patents and patent applications, including any drawings and appendices therein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application, drawing, or appendix was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0023] As used herein, the terms comprising, having, including and containing, and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements and/or method steps, even if a feature/component defined as a part thereof consists or consists essentially of specified feature(s)/component(s). The term consisting essentially of if used herein in connection with a compound, composition, use or method, denotes that additional elements and/or method steps may be present, but that these additions do not materially affect the manner in which the recited compound, composition, method or use functions. The term consisting of if used herein in connection with a feature of a composition, use or method, excludes the presence of additional elements and/or method steps in that feature. A compound, composition, use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to. A use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to.

[0024] A reference to an element by the indefinite article a does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements. The singular forms a, an, and the include plural referents unless the context clearly dictates otherwise. The use of the word a or an when used herein in conjunction with the term comprising may mean one, but it is also consistent with the meaning of one or more, at least one and one or more than one.

[0025] In this disclosure, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range including all whole numbers, all integers and, where suitable, all fractional intermediates (e.g., 1 to 5 may include 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5 etc.).

[0026] Unless otherwise specified, certain embodiments, various embodiments, an embodiment and similar terms includes the particular feature(s) described for that embodiment either alone or in combination with any other embodiment or embodiments described herein, whether or not the other embodiments are directly or indirectly referenced and regardless of whether the feature or embodiment is described in the context of a method, product, use, composition, compound, etcetera.

[0027] As used herein, the terms treat, treatment, therapeutic and the like includes ameliorating symptoms, reducing disease progression, improving prognosis and reducing recurrence.

[0028] The term subject refers to an animal (e.g. a mammal or a non-mammal animal). The subject may be a human or a non-human primate. The subject may be a laboratory mammal (e.g., mouse, rat, rabbit, hamster and the like). The subject may be an agricultural animal (e.g., equine, ovine, bovine, porcine, camelid and the like) or a domestic animal (e.g., canine, feline and the like). In some embodiments, the subject is a human.

[0029] The compounds disclosed herein may also include base-free forms, salts or pharmaceutically acceptable salts thereof. Unless otherwise specified, the compounds claimed and described herein are meant to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not they are explicitly represented herein.

[0030] The compounds disclosed herein may be shown as having one or more charged groups, may be shown with ionizable groups in an uncharged (e.g. protonated) state or may be shown without specifying formal charges. As will be appreciated by the person of skill in the art, the ionization state of certain groups within a compound (e.g. without limitation, CO.sub.2H, PO.sub.3H.sub.2, SO.sub.2H, SO.sub.3H, SO.sub.4H, OPO.sub.3H.sub.2 and the like) is dependent, inter alia, on the pKa of that group and the pH at that location. For example, but without limitation, a carboxylic acid group (i.e. COOH) would be understood to usually be deprotonated (and negatively charged) at neutral pH and at most physiological pH values, unless the protonated state is stabilized. Likewise, OSO.sub.3H (i.e. SO.sub.4H) groups, SO.sub.2H groups, SO.sub.3H groups, OPO.sub.3H.sub.2 (i.e. PO.sub.4H.sub.2) groups and PO.sub.3H groups would generally be deprotonated (and negatively charged) at neutral and physiological pH values.

[0031] As used herein, the terms salt and solvate have their usual meaning in chemistry. As such, when the compound is a salt or solvate, it is associated with a suitable counter-ion. It is well known in the art how to prepare salts or to exchange counter-ions. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g. without limitation, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or in an organic solvent, or in a mixture of the two. Counter-ions may be changed, for example, by ion-exchange techniques such as ion-exchange chromatography. All zwitterions, salts, solvates and counter-ions are intended, unless a particular form is specifically indicated.

[0032] In certain embodiments, the salt or counter-ion may be pharmaceutically acceptable, for administration to a subject. More generally, with respect to any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffers, stabilizing agents, salts, antioxidants, complexing agents, tonicity agents, cryoprotectants, lyoprotectants, suspending agents, emulsifying agents, antimicrobial agents, preservatives, chelating agents, binding agents, surfactants, wetting agents, non-aqueous vehicles such as fixed oils, or polymers for sustained or controlled release. See, for example, Berge et al. 1977. (J. Pharm Sci. 66:1-19), or RemingtonThe Science and Practice of Pharmacy, 21st edition (Gennaro et al editors. Lippincott Williams & Wilkins Philadelphia), each of which is incorporated by reference in its entirety.

[0033] As used herein, the expression C.sub.n where n is an integer (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and the like) or where n is defined as a range of integers (e.g. 1-20, 1-18, 2-15, 3-20, and the like) refers to the number of carbons in a compound, R-group, L-group, or substituent, or refers to the number of carbons plus heteroatoms in a compound, R-group, L-group, or substituent. A range of integers includes all integers in the range; e.g. the range 1-20 includes the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Unless otherwise defined, heteroatoms may include any, some or all possible heteroatoms. For example, in some embodiments, the heteroatoms may be selected from N, O, S, P and Se. In some embodiments, the heteroatoms are selected from N, S, or O. Such embodiments are non-limiting. The alternative expression Cy-Cz, where y and z are integers (e.g. C.sub.3-C.sub.15 and the like), is equivalent to C.sub.n where n is a range of integers from y to z.

[0034] The terms alkyl, alkylenyl, alkenylenyl, and alkynylenyl have their usual meanings in organic chemistry. For example, an alkyenylenyl has at least one carbon-carbon double bond, and may have any number of carbon-carbon single bonds. Similarly, an alkynylenyl has at least one carbon-carbon triple bond, and may have any number of carbon-carbon single bonds. The expressions alkylenyl, alkenylenyl and/or alkynylenyl and alkylenyl, alkenylenyl or alkynylenyl are intended to be equivalent and each includes hydrocarbon chains that can have any reasonable number or combination of carbon-carbon single bonds, double bonds, and triple bonds. These hydrocarbon chains can be linear, branched, cyclic, or any combination of linear and branched, linear and cyclic, cyclic and branched, branched and cyclic, or linear, branched and cyclic. Cyclic hydrocarbons may be nonaromatic, partially aromatic, or aromatic. Unless otherwise specified, the term cyclic includes single rings, multiple non-fused rings, fused rings, bridged rings, and combinations thereof.

[0035] The expression wherein any carbon . . . is optionally independently replaced by N, S, or O and other similar expressions means that the defined hydrocarbon (e.g. alkyl, alkylenyl, alkenylenyl, or alkynylenyl) includes zero, one, more than one, or any reasonable combination of two or more heteroatoms selected from N, S, and O. The above expression therefore expands the defined hydrocarbon to additionally encompass heteroalkyls, heteroalkylenyls, heteroalkenylenyls, and heteroalkynylenyls, etc. The person of skill in the art would understand that various combinations of different heteroatoms may be used. The expression wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O and other similar expressions means that any carbon in the defined hydrocarbon bonded to two other carbons (e.g. the underlined carbon in CCC), whether those bonds are single, double, or triple bonds, may be a heteroatom, but excludes heteroatoms bonded to other heteroatoms (e.g. excludes CNS, SSN, NSC, and the like).

[0036] Various R-groups (e.g. R.sup.1, R.sup.2, R.sup.3, etc.) and L-groups (e.g. L.sup.1, L.sup.2, L.sup.3, etc.) are defined in this disclosure. L-groups generally refer to linkages (e.g. S, NHC(O), C(O)NH, N(alkyl)-C(O), C(O)N(alkyl)-, NHC(O)NH, NHC(S)NH,

##STR00002##

[0037] If unspecified, the size of an R-group or L-group is what would be considered reasonable to the person of skill in the art. For example, but without limitation, if unspecified, the size of an alkyl may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more than 100 carbons in length, subject to the common general knowledge of the person of skill in the art.

[0038] Further, but without limitation, if unspecified, the size of a heteroalkyl may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more than 100 carbons and heteroatoms in length, subject to the common general knowledge of the person of skill in the art. In the context of the expression alkyl, alkenyl or alkynyl and similar expressions, the alkyl would be understood to be a saturated alkyl, and the alkenyl and the alkynyl would be understood to be unsaturated.

[0039] As used herein, in the context of an alkyl/heteroalkyl group of a compound, the term linear may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises a skeleton or main chain that does not split off into more than one contiguous chain. Non-limiting examples of linear alkyls include methyl, ethyl, n-propyl, and n-butyl.

[0040] As used herein, the term branched may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises a skeleton or main chain that splits off into more than one contiguous chain. The portions of the skeleton or main chain that split off in more than one direction may be linear, cyclic or any combination thereof. Non-limiting examples of a branched alkyl group include tert-butyl and isopropyl.

[0041] The term alkylenyl refers to a divalent analog of an alkyl group. In the context of the expression alkylenyl, alkenylenyl and/or alkynylenyl, and similar expressions, the alkylenyl would be understood to be a saturated alkylenyl, and the alkenylenyl and the alkynylenyl would be understood to be unsaturated. The term heteroalkylenyl refers to a divalent analog of a heteroalkyl group. The term heteroalkenylenyl refers to a divalent analog of a heteroalkenyl group.

[0042] The term heteroalkynylenyl refers to a divalent analog of a heteroalkynyl group.

[0043] As used herein, the term saturated when referring to a chemical entity may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises only single bonds, and may include linear, branched, and/or cyclic groups. Non-limiting examples of a saturated C.sub.1-C.sub.20 alkyl group may include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, n-hexyl, i-hexyl, 1,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, I-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1,2-triethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec-hexyl, t-hexyl, n-heptyl, i-heptyl, sec-heptyl, t-heptyl, n-octyl, i-octyl, sec-octyl, t-octyl, n-nonyl, i-nonyl, sec-nonyl, t-nonyl, n-decyl, i-decyl, sec-decyl, t-decyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, cyclooctanyl, cyclononanyl, cyclodecanyl, and the like. Unless otherwise specified, a C.sub.1-C.sub.20 alkylenyl therefore encompasses, without limitation, all divalent analogs of the above-listed saturated alkyl groups.

[0044] As used herein, the term unsaturated when referring to a chemical entity may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises at least one double or triple bond, and may include linear, branched, and/or cyclic groups. Non-limiting examples of a C.sub.2-C.sub.20 alkenyl group may include vinyl, allyl, isopropenyl, I-propene-2-yl, 1-butene-1-yl, 1-butene-2-yl, 1-butene-3-yl, 2-butene-1-yl, 2-butene-2-yl, octenyl, decenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononanenyl, cyclodecanenyl, and the like. Unless otherwise specified, a C.sub.1-C.sub.20 alkenylenyl therefore encompasses, without limitation, all divalent analogs of the above-listed alkenyl groups. Non-limiting examples of a C.sub.2-C.sub.20 alkynyl group may include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Unless otherwise specified, a C.sub.1-C.sub.20 alkynylenyl therefore encompasses, without limitation, all divalent analogs of the above-listed alkynyl groups.

[0045] Non-limiting examples of non-aromatic cyclic groups include cylcopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Non-limiting examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolydinyl, phthalimidyl, succinimidyl, oxiranyl, tetrahydropyranyl, oxetanyl, dioxanyl, thietanyl, thiepinyl, morpholinyl, oxathiolanyl, and the like.

[0046] Unless further specified, an aryl group includes both single aromatic rings as well as fused rings containing at least one aromatic ring. non-limiting examples of C.sub.3-C.sub.20 aryl groups include phenyl (Ph), pentalenyl, indenyl, naphthyl and azulenyl. Non-limiting examples of aromatic heterocyclic groups of similar size include pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pirazinyl, quinolinyl, isoquinolinyl, acridinyl, indolyl, isoindolyl, indolizinyl, purinyl, carbazolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, phenazinyl, phenanthrolinyl, perimidinyl, furyl, dibenzofuryl, xanthenyl, benzofuryl, thiophenyl, thianthrenyl, benzothiophenyl, phosphorinyl, phosphinolinyl, phosphindolyl, thiazolyl, oxazolyl, isoxazolyl, and the like.

[0047] As used herein, the term substituted is used as it would normally be understood to a person of skill in the art and generally refers to a compound or chemical entity that has one chemical group replaced with a different chemical group. Unless otherwise specified, a substituted alkyl, alkylenyl, alkenylenyl, or alkynylenyl has one or more hydrogen atom(s) independently replaced with an atom that is not hydrogen. For example, chloromethyl is a non-limiting example of a substituted alkyl, more particularly an example of a substituted methyl. Aminoethyl is another non-limiting example of a substituted alkyl, more particularly an example of a substituted ethyl. Unless otherwise specified, a substituted compound or group (e.g. R-group or L-group) may be substituted with any chemical group reasonable to the person of skill in the art. For example, but without limitation, a hydrogen bonded to a carbon or heteroatom (e.g. N) may be substituted with halide (e.g. F, I, Br, Cl), amine, amide, oxo, hydroxyl, thiol, phosphate, phosphonate, sulfate, SO.sub.2H, SO.sub.3H, alkyls, heteroalkyls, aryl, heteroaryl, ketones, carboxaldehyde, carboxylates, carboxamides, nitriles, monohalomethyl, dihalomethyl ortrihalomethyl. In some embodiments, each carbon may be independently substituted or unsubstituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid. In some embodiments, the amide substituent is C(O)NH.sub.2.

[0048] As used herein, the term unsubstituted is used as it would normally be understood to a person of skill in the art. Non-limiting examples of unsubstituted alkyls include methyl, ethyl, tert-butyl, pentyl and the like. The expression optionally substituted is used interchangeably with the expression unsubstituted or substituted. The expression optionally independently substituted means that each location may be substituted or may not be substituted, and when substituted each substituent may be the same or different.

[0049] In the structures provided herein, hydrogen may or may not be shown. In some embodiments, hydrogens (whether shown or implicit) may be protium (i.e. .sup.1H), deuterium (i.e. .sup.2H) or combinations of .sup.1H and .sup.2H. Methods for exchanging .sup.1H with .sup.2H are well known in the art. For solvent-exchangeable hydrogens, the exchange of .sup.1H with .sup.2H occurs readily in the presence of a suitable deuterium source, without any catalyst. The use of acid, base or metal catalysts, coupled with conditions of increased temperature and pressure, can facilitate the exchange of non-exchangeable hydrogen atoms, generally resulting in the exchange of all .sup.1H to .sup.2H in a molecule.

[0050] The compounds disclosed herein may be synthesized (at least in part) using peptide synthesis methods. Each amino acid residue in a peptide or peptidic region has both an amino group and a carboxylic acid group, either or both of which can be used for covalent attachment. In attaching to the remainder of the compound, the amino group and/or the carboxylic acid group may be converted to an amide or other structure; e.g. a carboxylic acid group of a first amino acid is converted to an amide (i.e. a peptide bond) when bonded to the amino group of a second amino acid. As such, amino acid residues may have the formula N(R.sup.a)R.sup.bC(O), where R.sup.a and R.sup.b are R-groups. R.sup.a will typically be hydrogen or methyl (or a different alkyl). The amino acid residues of a peptide may comprise typical peptide (amide) bonds and may further comprise bonds between side chain functional groups and the side chain or main chain functional group of another amino acid.

[0051] For example, the side chain carboxylate of one amino acid residue (e.g. Asp, Glu, etc.) in the peptide or peptidic region may be bonded to the amine of another amino acid residue (e.g. Dap, Dab, Orn, Lys) in the peptide or peptidic region. Further details are provided below. Unless otherwise indicated, an amino acid may be any amino acid, including proteinogenic and nonproteinogenic amino acids, alpha amino acids, beta amino acids, or any other amino acid. Non-limiting examples of nonproteinogenic amino acids are shown in Table 1 and include: D-amino acids (including without limitation any D-form of the following amino acids), ornithine (Orn), 3-(1-naphtyl)alanine (NaI), 3-(2-naphtyl)alanine (2-NaI), -aminobutyric acid, norvaline, norleucine (NIe), homonorleucine, beta-(1,2,3-triazol-4-yl)-L-alanine, 1,2,4-triazole-3-alanine, Phe(4-F), Phe(4-Cl), Phe(4-Br), Phe(4-1), Phe(4-NH.sub.2), Phe(4-NO.sub.2), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agp), -alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, 2-amino-3-(anthracen-2-yl) propanoic acid, 2-amino-3-(anthracen-9-yl)propanoic acid, 2-amino-3-(pyren-1-yl)propanoic acid, Trp(5-Br), Trp(5-OCH.sub.3), Trp(6-F), Trp(5-OH) or Trp(CHO), 2-aminoadipic acid (2-Aad), 3-aminoadipic acid (3-Aad), propargylglycine (Pra), homopropargylglycine (Hpg), beta-homopropargylglycine (Bpg), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), azidolysine (Lys(N.sub.3)), azido-ornithine (Orn(N.sub.3)), 2-amino-4-azidobutanoic acid Dab(N.sub.3), Dap(N.sub.3), 2-(5-azidopentyl)alanine, 2-(6-azidohexyl)alanine, 4-amino-1-carboxymethyl-piperidine (Pip), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp), and tranexamic acid. If not specified as an L- or D-amino acid, an amino acid shall be understood to encompass both L- and D-amino acids.

TABLE-US-00001 TABLE 1 List of non-limiting examples of non-proteinogenic amino acids. Any D-amino acid of a proteinogenic amino acid 10-aminodecanoic acid ornithine (Orn) 2-aminooctanoic acid 3-(1-naphtyl)alanine (Nal) 2-amino-3-(anthracen-2-yl)propanoic acid 3-(2-naphtyl)alanine (2-Nal) 2-amino-3-(anthracen-9-yl)propanoic acid -aminobutyric acid 2-amino-3-(pyren-1-yl)propanoic acid norvaline Trp(5-Br), norleucine (Nle) Trp(5-OCH.sub.3), homonorleucine Trp(6-F), beta-(1,2,3-triazol-4-yl)-L-alanine Trp(5-OH) 1,2,4-triazole-3-alanine Trp(CHO), Phe(4-F), Phe(2-F), Phe(3-F), 2-aminoadipic acid (2-Aad) Phe(4-Cl), Phe(2-Cl), Phe(3-Cl), 3-aminoadipic acid (3-Aad) Phe(4-Br), Phe(2-Br), Phe(3-Br), propargylglycine (Pra) Phe(4-1), Phe(2-1), Phe(2-1), homopropargylglycine (Hpg) Phe(4-NH.sub.2), Phe(2-NH.sub.2), Phe(3-NH.sub.2), beta-homopropargylglycine (Bpg) Phe(4-NO.sub.2), Phe(2-NO.sub.2), Phe(2-NO.sub.2), 2,3-diaminopropionic acid (Dap) homoarginine (hArg) 2,4-diaminobutyric acid (Dab) 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp) azidolysine (Lys(N.sub.3)) 2-(5-azidopentyl)alanine, 2-(6-azidohexyl)alanine azido-ornithine (Orn(N.sub.3)) 2-amino-4-guanidinobutyric acid (Agb) amino-4-azidobutanoic acid Dab(N.sub.3) 2-amino-3-guanidinopropionic acid (Agp) tranexamic acid -alanine 4-amino-1-carboxymethyl-piperidine (Pip) 4-aminobutyric acid NH.sub.2(CH.sub.2).sub.2O(CH.sub.2).sub.2C(O)OH 5-aminovaleric acid NH.sub.2(CH.sub.2).sub.2[O(CH.sub.2).sub.2].sub.2C(O)OH 6-aminohexanoic acid NH.sub.2(CH.sub.2).sub.2[O(CH.sub.2).sub.2].sub.3C(O)OH 7-aminoheptanoic acid NH.sub.2(CH.sub.2).sub.2[O(CH.sub.2).sub.2].sub.4C(O)OH 8-aminooctanoic acid NH.sub.2(CH.sub.2).sub.2[O(CH.sub.2).sub.2].sub.5C(O)OH 9-aminononanoic acid NH.sub.2(CH.sub.2).sub.2[O(CH.sub.2).sub.2].sub.6C(O)OH

[0052] The wavy line symbol shown through or at the end of a bond in a chemical formula (e.g. in the definitions L.sup.1, R.sup.3, L.sup.2, L.sup.3 and R.sup.alb of Formula I) is intended to define the group on one side of the wavy line, without modifying the definition of the structure on the opposite side of the wavy line. Where an R-group or L-group is bonded on two or more sides, any atoms shown outside the wavy lines are intended to clarify orientation of the defined group. As such, only the atoms between the two wavy lines constitute the definition of the R-group or L-group. When atoms are not shown outside the wavy lines (e.g. L.sup.1), or for a chemical group shown without wavy lines but does have bonds on multiple sides (e.g. C(O)NH, and the like), the chemical group should be read from left to right matching the orientation in the formula that the group relates to; e.g. for formula R.sup.aR.sup.bR.sup.c, the definition of R.sup.b as C(O)NH would be incorporated into the formula as R.sup.aC(O)NHR.sup.0 not as R.sup.aNHC(O)R.sup.0.

[0053] In various aspects, there is disclosed a compound wherein the compound has Formula I (as defined below) or wherein the compound is a salt or a solvate of Formula I:

##STR00003## [0054] wherein: [0055] R.sup.1 is R.sup.1aR.sup.1b, wherein R.sup.1a is absent, CH.sub.2, O, or S, and R.sup.1b is CH.sub.2 or CHF; [0056] R.sup.2 is (CH.sub.2).sub.3O, (CH.sub.2).sub.3, (CH.sub.2).sub.4, CH.sub.2O(CH.sub.2).sub.2, or CH.sub.2S(CH.sub.2).sub.2; [0057] L.sup.1 is S, N(R.sup.L1a)C(O), C(O)N(R.sup.L1a), NHC(O)NH, NHC(S)NH,

##STR00004## wherein R.sup.L1a is H, methyl, ethyl or a benzyl group with 0-4 substituents independently selected from halogen, OMe, or SMe; [0058] R.sup.3 is:

##STR00005## substituted with 0-4 substituents independently selected from C.sub.1-C.sub.4 alkyl, halogen, OMe, SMe, NH.sub.2, NO.sub.2, CN, or OH, and wherein 0-4 ring carbons are replaced with nitrogen; [0059] L.sup.2 is S, N(R.sup.L2a)C(O), C(O)N(R.sup.L2a), NHC(O)NH, NHC(S)NH,

##STR00006## wherein R.sup.L2a is H, methyl, or ethyl; [0060] each of n1 and n2 is 0-2; [0061] ring A has 0-3 double bonds, and is bonded at meta or para position; [0062] each of L.sup.3, L.sup.4, L.sup.5b, L.sup.5c, L.sup.6, and L.sup.7 is independently S, N(R.sup.L3a)C(O), C(O)N(R.sup.L3a), NHC(O)NH, NHC(S)NH,

##STR00007## [0063] wherein each R.sup.L3a is independently H, methyl, or ethyl; [0064] each of n3, n4, and n5 is independently 0-4; [0065] each R.sup.4 is independently a linear, branched, and/or cyclic C.sub.n6 alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n6 is independently 1-20, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid; and [0066] R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a linear, branched, and/or cyclic C.sub.n7 alkylenyl, alkenylenyl and/or alkynylenyl, wherein n7 is 1-20, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, wherein carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid, wherein one, two, or three of R.sup.5a, R.sup.5b, and R.sup.5c are optionally absent, wherein X.sup.br is C, CH, or N and wherein X.sup.br is separated from ring A by at least 4 atoms; [0067] each R.sup.6 and each R.sup.7 is independently a linear, branched, and/or cyclic C.sub.n8 alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n8 is independently 1-20, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid; [0068] R.sup.rad is a radiometal chelator, optionally bound by a radiometal, wherein R.sup.rad is separated from ring A by at least 7 atoms; and [0069] R.sup.alb is an albumin binder, wherein the albumin binder is: [0070] (CH.sub.2).sub.n9CH.sub.3 wherein n9 is 8-20; [0071] (CH.sub.2).sub.n10C(O)OH wherein n10 is 8-20; or

##STR00008##

wherein n11 is 1-4 and R.sup.8 is I, Br, F, Cl, H, OH, OCH.sub.3, NH.sub.2, NO.sub.2, or CH.sub.3; and [0072] R.sup.alb is separated from ring A by at least 7 atoms.

[0073] In some embodiments, the compound (of Formula I) has Formula II or is a salt or a solvate of Formula II:

##STR00009##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.L3a, R.sup.5b, R.sup.5c, R.sup.6, R.sup.7, R.sup.rad, R.sup.alb, L.sup.1, L.sup.2, L.sup.5b, L.sup.5c, L.sup.6, L.sup.7, ring A, n1, n2, n4, and n5 are as defined in Formula I, or as defined in any other embodiment(s) defined herein. In some of these embodiments: R.sup.1 is CH.sub.2CH.sub.2 or CHF. In some of these embodiments, R.sup.2 is (CH.sub.2).sub.4. In some of these embodiments, L.sup.1 is NHC(O). In some of these embodiments, R.sup.3 is

##STR00010##

optionally wherein R.sup.3 is

##STR00011##

In some of these embodiments, L.sup.2 is NHC(O). In some of these embodiments, n1 is 0; ring A has 0 double bonds and is bonded at para position, optionally wherein ring A is

##STR00012##

In some of these embodiments, n2 is 0 or 1. In some of these embodiments, each R.sup.L3a is H. In some of these embodiments, X.sup.br is N or CH. In some of these embodiments: R.sup.5b is (CH.sub.2).sub.4 and R.sup.5c is absent; or R.sup.5c is (CH.sub.2).sub.4 and R.sup.5b is absent. In some of these embodiments, L.sup.5b is NHC(O). In some of these embodiments, L.sup.5c is NHC(O). In some of these embodiments, L.sup.5b is NHC(O). In some of these embodiments, n4 is 0 or 1, and R.sup.6when presentis methylene. In some of these embodiments, n5 is 0 or 1, and R.sup.7when presentis methylene. In some of these embodiments, L.sup.6when presentis NHC(O). In some of these embodiments, L.sup.7when presentis NHC(O). In some of these embodiments, R.sup.alb is

##STR00013##

wherein n11 is 3 and R.sup.a is OCH.sub.3 or NO.sub.2. In some of these embodiments, R.sup.rad is DOTA or a DOTA derivative.

[0074] In some embodiments, R.sup.1 is R.sup.1aR.sup.1b, wherein R.sup.1a is absent or CH.sub.2, and R.sup.1b is CH.sub.2 or CHF; [0075] R.sup.2 is (CH.sub.2).sub.3O, (CH.sub.2).sub.3, (CH.sub.2).sub.4, or CH.sub.2O(CH.sub.2).sub.2; [0076] L.sup.1 is N(R.sup.L1a)C(O), C(O)N(R.sup.L1a), or NHC(O)NH, wherein R.sup.L1a is H or methyl; [0077] R.sup.3 is:

##STR00014## [0078] L.sup.2 is N(R.sup.L2a)C(O), C(O)N(R.sup.L2a), NHC(O)NH, wherein R.sup.L2a is H, or methyl; [0079] each of n1 and n2 is 0-2; [0080] ring A has 0 bonds, and is bonded at meta or para position; [0081] each of L.sup.3, L.sup.4, L.sup.5b, L.sup.5c, L.sup.6, and L.sup.7 is independently N(R.sup.L3a)C(O), C(O)N(R.sup.L3a), or NHC(O)NH, wherein each R.sup.L3a is independently H, methyl, or ethyl; [0082] each of n3, n4, and n5 is independently 0-4; [0083] each R.sup.4 is independently a linear C.sub.1-C.sub.10 alkylenyl; [0084] R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a linear, branched, and/or cyclic C.sub.1-C.sub.20 alkylenyl, alkenylenyl and/or alkynylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, wherein carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid, wherein one, two, or three of R.sup.5a, R.sup.5b, and R.sup.5c are optionally absent, wherein X.sup.br is N or CH, and wherein X.sup.br is separated from ring A by at least 4 atoms; [0085] each R.sup.6 and each R.sup.7 is independently a linear, branched, and/or cyclic C.sub.1-C.sub.20 alkylenyl, alkenylenyl and/or alkynylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid; [0086] R.sup.rad is a radiometal chelator, optionally bound by a radiometal, wherein R.sup.rad is separated from ring A by at least 7 atoms; and R.sup.alb is:

##STR00015## wherein n11 is 1-4 and R.sup.8 is I, Br, F, Cl, H, OH, OCH.sub.3, NH.sub.2, NO.sub.2, or CH.sub.3.

[0087] In another embodiment, R.sup.2 is (CH.sub.2).sub.3, or (CH.sub.2).sub.4; [0088] L.sup.1 is N(R.sup.L1a)C(O), or C(O)N(R.sup.L1a), wherein R.sup.L1a is H or methyl; [0089] R.sup.3 is:

##STR00016## [0090] L.sup.2 is N(R.sup.L2a)C(O), or C(O)N(R.sup.L2a), wherein R.sup.L2a is H, or methyl; [0091] each of n1 and n2 is 0-1; [0092] each of L.sup.3, L.sup.4, L.sup.5b, L.sup.5c, L.sup.6, and L.sup.7 is independently N(R.sup.L3a)C(O), or C(O)N(R.sup.L3a), wherein each R.sup.L3a is independently H or methyl; [0093] each R.sup.4 is independently a linear C.sub.1-C.sub.10 alkylenyl; [0094] R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a linear, branched, and/or cyclic C.sub.1-C.sub.10 alkylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by O, wherein carbons are optionally independently substituted with oxo, hydroxyl, amine, amide, or carboxylic acid, wherein one, two, or three of R.sup.5a, R.sup.5b, and R.sup.5c are optionally absent, wherein X.sup.br is N or CH and wherein X.sup.br is separated from ring A by at least 4 atoms; [0095] each R.sup.6 and each R.sup.7 is independently a linear, branched, and/or cyclic C.sub.1-C.sub.10 alkylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, amine, amide, urea, carboxylic acid; R.sup.alb is:

##STR00017## wherein n11 is 1-4 and R.sup.8 is OCH.sub.3, or NO.sub.2.

[0096] In another specific embodiment, L.sup.3 is NHC(O). In another specific embodiment, L.sup.4 is NHC(O). In another specific embodiment, R.sup.4 is methylene. In another specific embodiment, n3 is 1-4. In another specific embodiment, n3 is 1-2. In another specific embodiment, n3 is 1. In another specific embodiment, n2 is 0-1. In another specific embodiment, n2 is 1. In another specific embodiment, R.sup.5a is absent. In another specific embodiment, R.sup.5a is methylene.

[0097] In some embodiments, R.sup.1a is absent. In some embodiments, R.sup.1a is CH.sub.2. In some embodiments, R.sup.1a is O. In some embodiments, R.sup.1a is S.

[0098] In some embodiments, R.sup.1b is CH.sub.2. In some embodiments, R.sup.1b is CHF.

[0099] In some embodiments, R.sup.1 is CH.sub.2. In some embodiments, R.sup.1 is CHF. In some embodiments, R.sup.1 is CH.sub.2CH.sub.2. In some embodiments, R.sup.1 is CH.sub.2CHF. In some embodiments, R.sup.1 is OCH.sub.2. In some embodiments, R.sup.1 is OCHF. In some embodiments, R.sup.1 is SCH.sub.2. In some embodiments, R.sup.1 is SCHF.

[0100] In some embodiments, R.sup.2 is (CH.sub.2).sub.3O. In some embodiments, R.sup.2 is (CH.sub.2).sub.3. In some embodiments, R.sup.2 is (CH.sub.2).sub.4. In some embodiments, R.sup.2 is CH.sub.2O(CH.sub.2).sub.2. In some embodiments, R.sup.2 is CH.sub.2S(CH.sub.2).sub.2.

[0101] In some embodiments, L.sup.1 is N(R.sup.L1a)C(O) or C(O)N(R.sup.L1a) wherein R.sup.L1a is as defined in Formula I. In some such embodiments, R.sup.L1a is H. In other such embodiments, R.sup.L1a is methyl. In other such embodiments, R.sup.L1a is ethyl. In yet other such embodiments, R.sup.L1a is a benzyl group with 0-4 substituents independently selected from halogen, OMe, or SMe. In yet other such embodiments, R.sup.L1a is a benzyl group. In some embodiments, L.sup.1 is N(R.sup.L1a)C(O) or (O)N(R.sup.L1a) wherein L.sup.1a is H or methyl. In some embodiments, L.sup.1 is NHC(O). In some embodiments, L.sup.1 is C(O)NH.

[0102] In some embodiment, R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a linear or branched C.sub.1-C.sub.20 alkylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by 0, wherein carbons are optionally independently substituted with oxo, hydroxyl, amine, amide, or carboxylic acid, wherein one, two, or three of R.sup.5a, R.sup.5b, and R.sup.5c are optionally absent, wherein X.sup.br is N or CH and wherein X.sup.br is separated from ring A by at least 4 atoms. In another specific embodiment, the R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a linear or branched C.sub.1-C.sub.10 alkylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by O. In another specific embodiment, 1, 2, 3 or 4 carbons are replaced by O.

[0103] In some embodiments, L.sup.1 is S. In some embodiments, L.sup.1 is NHC(O)NH. In some embodiments, L.sup.1 is NHC(S)NH. In some embodiments, L.sup.1 is

##STR00018##

In some embodiments, L.sup.1 is

##STR00019##

In some embodiments, L.sup.1 is

##STR00020##

In some embodiments, L.sup.1 is

##STR00021##

[0104] In some embodiments, R.sup.3 is:

##STR00022##

substituted with 0-4 substituents independently selected from C.sub.1-C.sub.4 alkyl, halogen, OMe, SMe, NH.sub.2, NO.sub.2, CN, or OH, and wherein 0-4 ring carbons are replaced with nitrogen; in some such embodiments, the rings are unsubstituted and contain a single nitrogen. In some embodiments, R.sup.3 is:

##STR00023##

substituted with 0-4 substituents independently selected from C.sub.1-C.sub.4 alkyl, halogen, OMe, SMe, NH.sub.2, NO.sub.2, CN, or OH, and wherein 0-4 ring carbons are replaced with nitrogen; in some such embodiments, the rings are unsubstituted and contain a single nitrogen. In some embodiments, R.sup.3 is:

##STR00024##

In some embodiments, R.sup.3 is:

##STR00025##

In some embodiments, R.sup.3 is:

##STR00026##

In some embodiments, R.sup.3 is:

##STR00027##

[0105] In some embodiments, L.sup.2 is N(R.sup.L2a)C(O) or C(O)N(R.sup.L2a) wherein R.sup.L2a is as defined in Formula I. In some such embodiments, R.sup.L2a is H. In other such embodiments, R.sup.L2a is methyl. In other such embodiments, R.sup.L2a is ethyl. In yet other such embodiments, R.sup.L2a is a benzyl group with 0-4 substituents independently selected from halogen, OMe, or SMe. In yet other such embodiments, R.sup.L2a is a benzyl group. In some embodiments, L.sup.2 is N(R.sup.L2a)C(O) or (O)N(R.sup.L2a) wherein L.sup.2a is H or methyl. In some embodiments, L.sup.2 is NHC(O). In some embodiments, L.sup.2 is C(O)NH.

[0106] In some embodiments, L.sup.2 is S. In some embodiments, L.sup.2 is NHC(O)NH. In some embodiments, L.sup.2 is NHC(S)NH. In some embodiments, L.sup.2 is

##STR00028##

In some embodiments, L.sup.2 is

##STR00029##

In some embodiments, L.sup.2 is

##STR00030##

In some embodiments, L.sup.2 is

##STR00031##

[0107] In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments n1 is 2.

[0108] In some embodiments, ring A has 0 double bonds (i.e. all single bonds). In some embodiments, ring A has 1 double bond. In some embodiments, ring A has 2 double bonds. In some embodiments, ring A has 3 double bonds. In some embodiments, ring A is bonded at meta position. In some embodiments, ring A is bonded at para position. In some embodiments, ring A has 0 double bonds and is bonded at para position. In some embodiments, ring A is

##STR00032##

In some embodiments, ring A is

##STR00033##

[0109] In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments n2 is 2.

[0110] In some embodiments, L.sup.3 is N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a) wherein R.sup.L3a is as defined in Formula I. In some such embodiments, R.sup.L3a is H. In other such embodiments, R.sup.L3a is methyl. In other such embodiments, R.sup.L3a is ethyl. In some embodiments, L.sup.3 is N(R.sup.L3a)C(O) or (O)N(R.sup.L3a) wherein R.sup.L3a is H or methyl. In some embodiments, L.sup.3 is NHC(O). In some embodiments, L.sup.3 is C(O)NH. In some embodiments, L.sup.3 is S. In some embodiments, L.sup.3 is NHC(O)NH. In some embodiments, L.sup.3 is NHC(S)NH. In some embodiments, L.sup.3 is

##STR00034##

In some embodiments, L.sup.3 is

##STR00035##

In some embodiments, L.sup.3 is

##STR00036##

In some embodiments, L.sup.3 is

##STR00037##

[0111] In some embodiments, R.sup.1 is CH.sub.2CH.sub.2 and R.sup.2 is (CH.sub.2).sub.4. In some such embodiments, L.sup.1 is NHC(O). In some such embodiments, R.sup.3 is

##STR00038##

optionally wherein R.sup.3 is

##STR00039##

In some such embodiments, L.sup.2 is NHC(O). In some such embodiments, n1 is 0; ring A has 0 double bonds and is bonded at para position, optionally wherein ring A is

##STR00040##

In some such embodiments, n2 is 0 or 1. In some such embodiments, L.sup.3 is NHC(O).

[0112] In some embodiments, n3 is 0. In some embodiments, n3 is 1. In some embodiments n3 is 2. In some embodiments, n3 is 3. In some embodiments n3 is 4.

[0113] In embodiments where n3 is not zero, each R.sup.4 is independently a linear, branched, and/or cyclic C.sub.n6 alkylenyl, alkenylenyl and/or alkynylenyl, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted. In some embodiments, each n6 is independently 1-15 or 1-10. In alternative embodiments, each n6 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, each R.sup.4 is independently a C.sub.n6 alkylenyl wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted; in some such embodiments, n3 is 1. In some embodiments, n3 is 1 and R.sup.4 is C.sub.1-C.sub.5 alkylenyl, optionally methylene. In some embodiments, each R.sup.4 is independently C(R.sup.aa)H, wherein each R.sup.aa is independently the sidechain of a proteinogenic amino acid or the sidechain of an alpha amino acid from Table 1. In some embodiments, each R.sup.4 is independently a proteinogenic amino acid or an amino acid from Table 1 omitting the backbone amino and carboxylic acid groups of the amino acid.

[0114] In some embodiments where n3 is not zero, each L.sup.4 is independently N(R.sup.L4a)C(O) or C(O)N(R.sup.L4a) wherein each R.sup.L4a is independently H, methyl, or ethyl. In other such embodiments, each R.sup.L4a is independently H or methyl. In other such embodiments, at least one R.sup.L4a is ethyl. In some embodiments, each L.sup.4 is independently NHC(O) or C(O)NH. In some embodiments, each L.sup.4 is NHC(O). In some embodiments, at least one L.sup.4 is S. In some embodiments, at least one L.sup.4 is NHC(O)NH. In some embodiments, at least one L.sup.4 is NHC(S)NH. In some embodiments, at least one L.sup.4 is

##STR00041##

In some embodiments, at least one L.sup.4 is

##STR00042##

In some embodiments, at least one L.sup.4 is

##STR00043##

In some embodiments, at least one L.sup.4 is

##STR00044##

[0115] In some embodiments, n3 is 1, R.sup.4 is methylene and L.sup.4 is NHC(O). In some such embodiments, L.sup.3 is NHC(O). In some such embodiments, n2 is 1.

[0116] In some embodiments where n3 is not zero, each L.sup.4 is independently N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a) wherein each R.sup.L3a is independently H, methyl, or ethyl. In other such embodiments, each R.sup.L4a is independently H or methyl. In other such embodiments, at least one R.sup.L3a is ethyl.

[0117] X.sup.br is a branching atom, i.e. the point where the linker diverges from a single chain to two chains to connect both R.sup.rad and R.sup.alb to the PSMA-binding moiety. In some embodiments, X.sup.br is N, C or CH. In some embodiments, X.sup.br is CH. In other embodiments, X.sup.br is N.

[0118] In some embodiments, X.sup.br is separated from ring A by at least 4 ms, at least 5 atoms, at least 6 atoms, at least 7 atoms, at least 8 atoms, at least 9 atoms, or at least 10 atoms. The expression X.sup.br is separated from ring A by at least [number] atoms refers to the number of atoms that form a contiguous chain by the shortest route between X.sup.br and ring A, and excluding X.sup.br and ring A atoms from the atom count. The expression by the shortest route in this context refers to the possibility for a ring to be included in the atoms separating X.sup.br and ring A, such that there are two or more non-equivalent routes to count atoms in a contiguous chain; in such a situation, the shortest route is counted. The number of atoms separating X.sup.br and ring A does not include hydrogens and does not include any non-hydrogen atoms branching off the shortest route. For example, in the structure CCZ02017 (see Examples for its chemical structure), the number of atoms separating X.sup.br and ring A is 6, and excludes the two amide oxygens and excludes all hydrogens.

[0119] In some embodiments, X.sup.br is separated from ring A by 6 atoms. In some embodiments, X.sup.br is separated from ring A by 5 atoms. In some embodiments, X.sup.br is separated from ring A by 4 atoms.

[0120] As defined by Formula I, R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a C.sub.n7 alkylenyl, alkenylenyl and/or alkynylenyl, wherein n7 is 1-20 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), wherein any carbon bonded to two other carbons may be independently replaced by N, S, or O heteroatoms. In some embodiments, R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms a C.sub.n7 alkylenyl. In some embodiments, n7 is 1-15 or 1-10. In some embodiments, 1 carbon is replaced by N, S, or O. In other embodiments, 2, 3, 4, or 5 carbons are each independently replaced by N, S, or O. In some embodiments, the carbons are unsubstituted. In other embodiments, 1 carbon is substituted. In other embodiments, 2 or 3 carbons are independently substituted. The substitutions are as defined in Formula I. In some embodiments, the substitutions are independently selected from one or more than one of hydroxyl, sulfhydryl, amine, guanidino, and/or carboxylic acid. In some embodiments, R.sup.5a is absent. In some embodiments, R.sup.5b is absent. In some embodiments, R.sup.5c is absent. In some embodiments, R.sup.5a and R.sup.5b are absent. In some embodiments, R.sup.5a and R.sup.5c are absent. In some embodiments, R.sup.5b and R.sup.5c are absent. In some embodiments, all three of R.sup.5a, R.sup.5b, and R.sup.5c are absent. In some embodiments, R.sup.5a is C.sub.1-C.sub.6 alkylenyl, optionallly (CH.sub.2).sub.1-4. In some embodiments, R.sup.5b is C.sub.1-C.sub.6 alkylenyl, optionallly (CH.sub.2).sub.1-4. In some embodiments, R.sup.5c is C.sub.1-C.sub.6 alkylenyl, optionallly (CH.sub.2).sub.1-4.

[0121] In some embodiments: R.sup.5a is absent or C.sub.1-C.sub.6 alkylenyl, optionally (CH.sub.2).sub.1-4; R.sup.5b is absent or C.sub.1-C.sub.6 alkylenyl, optionally (CH.sub.2).sub.1-4; R.sup.5c is absent or C.sub.1-C.sub.6 alkylenyl, optionally (CH.sub.2).sub.1-4; and X.sup.br is N, C or CH; wherein any of R.sup.5a, R.sup.5b or R.sup.5c is absent. In some embodiments, R.sup.5aX.sup.br(R.sup.5c)R.sup.5b forms:

##STR00045##

wherein each of n12a, n12b, and n12c is independently 0-4. In some embodiments, R.sup.5aX.sup.br(R.sup.5c)R.sup.5b is

##STR00046##

[0122] In some embodiments, L.sup.5b is N(R.sup.L5b)C(O) or C(O)N(R.sup.L5b) wherein R.sup.L5b is H, methyl, or ethyl. In some such embodiments, R.sup.L5b is H. In other such embodiments, R.sup.L5b is methyl. In other such embodiments, R.sup.L5b is ethyl. In some embodiments, L.sup.5b is NHC(O). In some embodiments, L.sup.5b is C(O)NH. In some embodiments, L.sup.5b is S.

[0123] In some embodiments, L.sup.5b is N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a) wherein R.sup.L3a is H, methyl, or ethyl. In some such embodiments, R.sup.L3a is H. In other such embodiments, R.sup.L3a is methyl. In other such embodiments, R.sup.L3a is ethyl. In some embodiments, L.sup.5b is NHC(O).

[0124] In some embodiments, L.sup.5b is NHC(O)NH. In some embodiments, L.sup.5b is NHC(S)NH. In some embodiments, L.sup.5b is

##STR00047##

In some embodiments, L.sup.5b is

##STR00048##

In some embodiments, L.sup.5b is

##STR00049##

In some embodiments, L.sup.5b is

##STR00050##

[0125] In some embodiments, L.sup.5c is N(R.sup.L50)C(O) or C(O)N(R.sup.L50) wherein R.sup.L5c is H, methyl, or ethyl. In other such embodiments, R.sup.L5c is methyl. In other such embodiments, R.sup.L5c is ethyl. In some embodiments, L.sup.5c is NHC(O). In some embodiments, L.sup.5c is C(O)NH. In some embodiments, L.sup.5c is S.

[0126] In some embodiments, L.sup.5c is N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a) wherein R.sup.L3a is H, methyl, or ethyl. In other such embodiments, R.sup.L3a is methyl. In other such embodiments, R.sup.L3a is ethyl. In some embodiments, L.sup.5c is NHC(O). In some embodiments, L.sup.5c is C(O)NH. In some embodiments, L.sup.5c is S. In some embodiments, L.sup.5c is NHC(O)NH.

[0127] In some embodiments, L.sup.5c is NHC(O)NH. In some embodiments, L.sup.5c is NHC(S)NH.

[0128] In some embodiments, L.sup.5c is

##STR00051##

In some embodiments, L.sup.5c is

##STR00052##

some embodiments, L.sup.5c is

##STR00053##

In some embodiments, L.sup.5c is

##STR00054##

[0129] In some embodiments: n3 is 0; R.sup.5a is methylene; X.sup.br is N or CH; and R.sup.5b is (CH.sub.2).sub.4 and R.sup.5c is absent, or R.sup.5c is (CH.sub.2).sub.4 and R.sup.5b is absent. In some such embodiments, L.sup.5b is NHC(O). In some such embodiments, L.sup.5c is NHC(O). L.sup.5b and L.sup.5c may each be NHC(O).

[0130] In some embodiments, n4 is 0. In some embodiments, n4 is 1. In some embodiments n4 is 2. In some embodiments, n4 is 3. In some embodiments n4 is 4.

[0131] In embodiments where n4 is not zero, each R.sup.6 is independently a linear, branched, and/or cyclic C.sub.n8a alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n8a is independently 1-20, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted. In some embodiments, each n8a is independently 1-15 or 1-10. In alternative embodiments, each n8a is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, each R.sup.6 is independently a C.sub.n8a alkylenyl wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted; in some such embodiments, n4 is 1. In some embodiments, n4 is 1 and R.sup.6 is C.sub.1-C.sub.5 alkylenyl, optionally methylene or (CH.sub.2).sub.1-4. In some embodiments, each R.sup.6 is independently C(R.sup.aa)H, wherein each R.sup.aa is independently the sidechain of a proteinogenic amino acid or the sidechain of an alpha amino acid from Table 1. In some embodiments, each R.sup.6 is independently a proteinogenic amino acid or an amino acid from Table 1 omitting the backbone amino and carboxylic acid groups of the amino acid.

[0132] In some embodiments where n4 is not zero, each L.sup.6 is independently N(R.sup.L6a)C(O) or C(O)N(R.sup.L6a) wherein each R.sup.L6a is independently H, methyl, or ethyl. In other such embodiments, each R.sup.L6a is independently H or methyl. In some embodiments where n4 is not zero, each L.sup.6 is independently N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a) wherein each R.sup.L3a is independently H, methyl, or ethyl. In other such embodiments, each R.sup.L3a is independently H or methyl. In other such embodiments, at least one R.sup.L6a is ethyl. In some embodiments, each L.sup.6 is independently-NHC(O) or C(O)NH. In some embodiments, each L.sup.6 is NHC(O). In some embodiments, at least one L.sup.6 is S. In some embodiments, at least one L.sup.6 is NHC(O)NH. In some embodiments, L.sup.6 is NHC(S)NH. In some embodiments, at least one L.sup.6 is

##STR00055##

In some embodiments, at least one L.sup.6 is

##STR00056##

In some embodiments, at least one L.sup.6 is

##STR00057##

In some embodiments, at least one L.sup.6 is

##STR00058##

[0133] In some embodiments, n5 is 0. In some embodiments, n5 is 1. In some embodiments n5 is 2. In some embodiments, n5 is 3. In some embodiments n5 is 4.

[0134] In embodiments where n5 is not zero, each R.sup.7 is independently a linear, branched, and/or cyclic C.sub.n8b alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n8b is independently 1-20, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted. In some embodiments, each n8b is independently 1-15 or 1-10. In alternative embodiments, each n8b is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, each R.sup.7 is independently a C.sub.n8b alkylenyl wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted; in some such embodiments, n5 is 1. In some embodiments, n5 is 1 and R.sup.7 is C.sub.1-C.sub.5 alkylenyl, optionally methylene or (CH.sub.2).sub.1-4. In some embodiments, each R.sup.7 is independently C(R.sup.aa)H, wherein each R.sup.aa is independently the sidechain of a proteinogenic amino acid or the sidechain of an alpha amino acid from Table 1. In some embodiments, each R.sup.6 is independently a proteinogenic amino acid or an amino acid from Table 1 omitting the backbone amino and carboxylic acid groups of the amino acid.

[0135] In some embodiments where n5 is not zero, each L.sup.7 is independently N(R.sup.L7a)C(O) or C(O)N(R.sup.L7a) wherein each R.sup.L7a is independently H, methyl, or ethyl. In other such embodiments, each R.sup.L7a is independently H or methyl. In other such embodiments, at least one R.sup.L7a is ethyl. In some embodiments, each L.sup.7 is independently NHC(O) or C(O)NH. In some embodiments, each L.sup.7 is NHC(O). In some embodiments where n5 is not zero, each L.sup.7 is independently N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a) wherein each R.sup.L3a is independently H, methyl, or ethyl. In other such embodiments, each R.sup.L3a is independently H or methyl. In other such embodiments, at least one R.sup.L3a is ethyl. In some embodiments, each L.sup.7 is independently NHC(O) or C(O)NH. In some embodiments, each L.sup.7 is NHC(O). In some embodiments, at least one L.sup.7 is S. In some embodiments, L.sup.7 is NHC(O)NH.

[0136] In some embodiments, L.sup.7 is NHC(S)NH. In some embodiments, at least one L.sup.7 is

##STR00059##

[0137] In some embodiments, at least one L.sup.7 is

##STR00060##

In some embodiments, at least one L.sup.7 is

##STR00061##

In some embodiments, at least one L.sup.7 is

##STR00062##

[0138] R.sup.rad is a radiometal chelator that is separated from ring A by at least 7 atoms. The expression R.sup.rad is separated from ring A by at least [number] atoms refers to the number of atoms that form a contiguous chain by the shortest route between R.sup.rad and ring A, and excluding R.sup.rad and ring A atoms from the atom count. The expression by the shortest route in this context refers to the possibility for a ring to be included in the atoms separating R.sup.rad and ring A, such that there are two or more non-equivalent routes to count atoms in a contiguous chain; in such a situation, the shortest route is counted. The number of atoms separating R.sup.rad and ring A does not include hydrogens and does not include any non-hydrogen atoms branching off the shortest route. For example, in the structure CCZ02017 (see Examples for chemical structure), the number of atoms separating R.sup.rad and ring A is 13 (including the linking amide attached to DOTA), and excludes the three amide oxygens, excludes the branch of the linker connecting R.sup.alb, and excludes all hydrogens. In some embodiments, R.sup.rad is separated from ring A by at least 7 atoms, at least 8 atoms, at least 9 atoms, at least 10 atoms, at least 11 atoms, at least 12 atoms, at least 13 atoms, at least 14 atoms, or at least 15 atoms. In some embodiments, R.sup.rad is separated from ring A by 7-18 atoms (e.g. 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 atoms). In some embodiments, R.sup.rad is bound by a radiometal. In some embodiments, the radiometal is not bound to R.sup.rad.

[0139] The various embodiments described herein can also be combined to form more specific embodiments as needed. For example, in a specific embodiment, ring A is

##STR00063##

R.SUP.2 .is

[0140] (CH.sub.2).sub.4; R.sup.3 is:

##STR00064## n1 is 0; L.sup.1 is N(R.sup.L1a)C(O), or C(O)N(R.sup.L1a), wherein R.sup.L1a is H; L.sup.2 is N(R.sup.L2a)C(O), or C(O)N(R.sup.L2a), wherein R.sup.L2a is H; and R.sup.1 is R.sup.1aR.sup.1b, wherein R.sup.1a is CH.sub.2, and R.sup.1b is CH.sub.2 or CHF.

[0141] In another specific embodiment, R.sup.5c is absent; L.sup.5c is N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; R.sup.7 is methylene; L.sup.7 is N(R.sup.L3a)C(O) or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; [0142] n5 is 1; and R.sup.alb is:

##STR00065## wherein n11 is 3 and R.sup.8 is OCH.sub.3, or NO.sub.2.

[0143] In another specific embodiment, n2 is 0 or 1; L.sup.3 is N(R.sup.L3a)C(O), or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; R.sup.4 is methylene; L.sup.4 is N(R.sup.L3a)C(O), or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; n3 is 1; R.sup.5a is absent; and X.sup.br is CH.

[0144] In another specific embodiment, R.sup.5b is a linear C.sub.1-C.sub.6 alkylenyl; L.sup.5b is N(R.sup.L3a), C(O) or C(O)N(R.sup.L3a), wherein R.sup.L3a is H; R.sup.6 is methylene; L.sup.6 is N(R.sup.L3a)C(O) or O(O)N(R.sup.L3a), wherein R.sup.L3a is H; and n4 is 0-2.

[0145] In some embodiments, R.sup.rad is selected from Table 2, wherein R.sup.rad is optionally bound by a radiometal.

[0146] The radiometal chelator may be any radiometal chelator suitable for binding to the radiometal and which is functionalized for attachment to an amino group. Many suitable radiometal chelators are known, e.g. as summarized in Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290, which is incorporated by reference in its entirety. Non-limiting examples of radiometal chelators include chelators selected from the group consisting of: DOTA and derivatives; DOTAGA; NOTA; NODAGA; NODASA; CB-DO2A; 3p-C-DEPA; TCMC; DO3A; DTPA and DTPA analogues optionally selected from CHX-A-DTPA and 1B4M-DTPA; TETA; NOPO; Me-3,2-HOPO; CB-TE1A1P; CB-TE2P; MM-TE2A; DM-TE2A; sarcophagine and sarcophagine derivatives optionally selected from SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar; TRAP; AAZTA; DATA and DATA derivatives; H2-macropa or a derivative thereof; H.sub.2dedpa, H.sub.4octapa, H.sub.4py4pa, H.sub.4Pypa, H.sub.2azapa, H.sub.5decapa, and other picolinic acid derivatives; CP256; PCTA; C-NETA; C-NE3TA; HBED; SHBED; BCPA; CP256; YM103; desferrioxamine (DFO) and DFO derivatives; and H.sub.6phospa. Exemplary non-limiting examples of radiometal chelators and example radioisotopes chelated by these chelators are shown in Table 2. In Table 2, the functional groups for linkage are shown in their non-linked forms; the person of skill in the art would appreciate that once linked to the compounds disclosed herein, these linking functional groups would be modified (e.g. COOH or NH.sub.2 in the chelator would become an amide linkage when reacted with NH.sub.2 or COOH, respectively, in the linker). When counting the atoms separating R.sup.rad from ring A, the linkage atoms (or linkage-forming functional groups in Table 2) are not included in the atom count. In alternative embodiments, R.sup.rad comprises a radiometal chelator selected from those listed above or in Table 2 linked via a linkage-forming functional group (e.g. COOH, NH.sub.2, SH, and the like). One skilled in the art could replace any of the chelators listed herein with another chelator.

TABLE-US-00002 TABLE 2 Exemplary chelators and exemplary isotopes which bind said chelators. Chelator Isotopes [00066] Cu-64/67 In-111 Lu-177 Y-86/90 Bi-203/212/213 Pb-212 Ac-225 Gd-159 Yb-175 Ho-166 As-211 Sc-44/47 Pm-149 Pr-142 Sn-117m Sm-153 Tb-149/161 Er-165 Ra-223/224 Th-227 [00067] Cu-64/67 [00068] Pb-212 [00069] Bi-212/213 [00070] Cu-64/67 [00071] Cu-64/67 [00072] Cu-64/67 [00073] Cu-64/67 [00074] Cu-64/67 In-111 Sc-44/47 [00075] Cu-64/67 Lu-177 Y-86/90 Bi-213 Pb-212 [00076] Au-198/199 [00077] Rh-105 [00078] In-111 Sc-44/47 Lu-177 Y-86/90 Sn-117m Pd-109 [00079] In-111 Lu-177 Y-86/90 Bi-212/213 [00080] Cu-64/67 [00081] Cu-64/67 [00082] In-111 Lu-177 Y-86/90 Ac-225 [00083] Ac-225 [00084] In-111 Ac-225 [00085] In-111 Lu-177 Ac-225 [00086] In-111 Lu-177 Ac-225 [00087] In-111 [00088] In-111 [00089] Cu-64/67 [00090] Ac-225 [00091] Ac-225 Tb-161 [00092] Ac-225 Tb-161 Lu-177 [00093] Lu-177 [00094]

[0147] In some embodiments, the chelator is DOTA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2. In some embodiments, the chelator is CB-DO2A, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is TCMC, or a derivative thereof, linked via an amide (e.g. formed from one of the CONH.sub.2 groups shown in Table 2). In some embodiments, the chelator is 3p-C-DEPA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is p-NH.sub.2-Bn-Oxo-DO3A or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is TETA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is CB-TE2A, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is Diamsar, or a derivative thereof, linked via an amide (e.g. formed from one of the amino groups shown in Table 2), In some embodiments, the chelator is NOTA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is NETA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is HxTSE, or a derivative thereof, linked via an amide (e.g. formed from one of the amino groups shown in Table 2). In some embodiments, the chelator is P.sub.2N.sub.2Ph.sub.2, or a derivative thereof, linked via an amide (e.g. formed from one of the amino groups shown in Table 2). In some embodiments, the chelator is DTPA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is CHX-A00-DTPA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H.sub.2dedpa, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H.sub.2azapa, or a derivative thereof, linked via an amdie (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H.sub.4octapa, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H.sub.6phospa, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H.sub.4CHXoctapa, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H.sub.5decapa, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H.sub.4neunpa-p-Bn-NO2, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is SHBED, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is BPCA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is PCTA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H.sub.2-MACROPA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is Crown, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).

[0148] In some embodiments, the radiometal chelator is a derivative of a radiometal chelator shown in Table 2. A derivative may include, e.g. (1) modification of a functional group of the chelator (e.g. a carboxyl group, an amino group, etc.) or (2) attachment of a new functional group (e.g. attachment of an R-group to an ethylene carbon located between two nitrogen atoms, wherein the R-group is a functional group fused to a spacer). In some embodiments, a carboxyl functional group shown in Table 2 is replaced with azidopropyl ethylacetamide (e.g. azido-mono-amide-DOTA), butynylacetamide (e.g. butyne-DOTA), thioethylacetamide (e.g. DO3A-thiol), maleimidoethylacetamide (e.g. maleimido-mono-amide-DOTA), or N-hydroxysuccinimide ester (e.g. DOTA-NHS-ester). When linked, these derivative chelators can be linked either via an amide (formed from a remaining carboxyl group) or via C(O)NH(CH.sub.2).sub.2-3-(triazole) or C(O)NH(CH.sub.2).sub.2-3-(thiomaleimide). In other embodiments, a backbone carbon (e.g. in an ethylene positioned between two backbone nitrogen atoms) in the chelator ring is fused to an R-group containing a functional group, optionally wherein the R-group is (CH.sub.2).sub.1-3-(phenyl)-NCS or (CH.sub.2).sub.1-3-(phenyl)-NCO, optionally 1,4-isothiocyanatobenzyl; e.g. p-SCN-Bn-DOTA (S2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid), p-SCN-Bn-NOTA (2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid), and the like. When linked, these derivatives can form a urea linkage (formed from isocyanate) or a thiourea linkage (formed from isothiocyanate).

[0149] In some embodiments, the radiometal chelator is conjugated with a radioisotope (i.e. radiometal). The conjugated radioisotope may be, without limitation, .sup.165Er, .sup.212Bi, .sup.166Ho, .sup.149Pm, .sup.159Gd, .sup.105Rh, .sup.109Pd, .sup.198Au, .sup.199Au, .sup.175Yb .sup.142Pr, .sup.177Lu, .sup.111In, .sup.213Bi, .sup.212Pb, .sup.47Sc, .sup.90Y, .sup.225Ac, .sup.117mSn, .sup.153Sm, .sup.149Tb, .sup.161Tb, .sup.224Ra, .sup.227Th, .sup.223Ra, .sup.64Cu, .sup.67Cu, and the like. In some embodiments, the chelator is a chelator from Table 2 and the conjugated radioisotope is a radioisotope indicated in Table 2 as a binder of the particular chelator.

[0150] In some embodiments, the chelator is: DOTA or a derivative thereof, optionally conjugated with .sup.177Lu, .sup.111In .sup.213Bi, .sup.212Pb, .sup.47Sc, .sup.90Y, .sup.225Ac, .sup.117mSn, .sup.153Sm, .sup.149Tb, .sup.161Tb, .sup.165Er, .sup.224Ra, .sup.212Bi, .sup.227Th, .sup.223Ra, .sup.64Cu or .sup.67Cu; Crown optionally conjugated with .sup.225Ac, .sup.227Th or .sup.177Lu; .sup.153Sm, MACROPA optionally conjugated with .sup.225Ac; Me-3,2-HOPO optionally conjugated with .sup.227Th; H.sub.4py4pa optionally conjugated with .sup.225Ac; H.sub.4pypa optionally conjugated with .sup.177Lu; or DTPA optionally conjugated with .sup.111In.

[0151] In some embodiments, the chelator is TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), SarAr (1-N-(4-Aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), TRAP (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid), HBED (N,N-bis(2-hydroxybenzyl)-ethylenediamine-N,N-diacetic acid), 2,3-HOPO (3-hydroxypyridin-2-one), PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1 (15),11,13-triene-3,6,9,-triacetic acid), DFO (desferrioxamine), DTPA (diethylenetriaminepentaacetic acid), OCTAPA (N,N-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N-diacetic acid) or another picolinic acid derivative.

[0152] In some embodiments, the radiometal chelator is mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine diethyl ester, methylenediphosphonate, hexamethylpropyleneamineoxime, or hexakis(methoxy isobutyl isonitrile). In some of these embodiments, the chelator is bound by a radioisotope. In some such embodiments, the radioisotope is .sup.186Re or .sup.188Re. In some embodiments, the chelator is not bound by a radioisotope.

[0153] R.sup.alb is an albumin binder. In some embodiments, R.sup.alb is (CH.sub.2).sup.n9CH.sub.3 wherein n9 is 8-20; in alternative embodiments, n9 is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, R.sup.a1b is (CH.sub.2).sup.n10C(O)OH wherein n10 is 8-20; in alternative embodiments, n10 is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, R.sup.alb is

##STR00095##

wherein n11 is 1-4 and R.sup.8 is I, Br, F, Cl, H, OH, OCH.sub.3, NH.sub.2, NO.sub.2, or CH.sub.3; in alternative embodiments, n11 is 1, 2, 3, or 4. In some embodiments, n11 is 3. In some embodiments, R.sup.8 is OCH.sub.3 or NO.sub.2. In some embodiments, R.sup.alb is

##STR00096##

[0154] R.sup.alb is separated from ring A by at least 7 atoms. In some embodiments, R.sup.alb is separated from ring A by at least 4 atoms, at least 5 atoms, at least 6 atoms, at least 7 atoms, at least 8 atoms, at least 9 atoms, or at least 10 atoms. The expression R.sup.alb is separated from ring A by at least [number] atoms refers to the number of atoms that form a contiguous chain by the shortest route between R.sup.alb and ring A, and excluding R.sup.alb and ring A atoms from the atom count. The expression by the shortest route in this context refers to the possibility for a ring to be included in the atoms separating R.sup.alb and ring A, such that there are two or more non-equivalent routes to count atoms in a contiguous chain; in such a situation, the shortest route is counted. The number of atoms separating R.sup.alb and ring A does not include hydrogens and does not include any non-hydrogen atoms branching off the shortest route. For example, in the structure CCZ02017 (see Examples for chemical structure), the number of atoms separating R.sup.alb and ring A is 12, and excludes the four amide oxygens, excludes the branch of the linker that links R.sup.rad, and excludes all hydrogens.

[0155] In some embodiments, R.sup.alb is separated from ring A by 7-18 atoms, and R.sup.rad is separated from ring A by 7-18 atoms. In some embodiments, R.sup.alb and R.sup.rad are each separated from ring A by 10-11 atoms. In some such embodiments, X.sup.br is separated from ring A by 4-6, optionally 6 atoms.

[0156] In some embodiments, the compound (of Formula I) has Formula II or is a salt or a solvate of Formula II:

##STR00097##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.L3a, R.sup.5b, R.sup.5c, R.sup.6, R.sup.7, R.sup.rad, R.sup.alb, L.sup.1, L.sup.2, L.sup.5b, L.sup.5c, L.sup.6, L.sup.7, ring A, n1, n2, n4, and n5 are as defined in Formula I, or as defined in any other embodiment(s) defined herein. In some of these embodiments: R.sup.1 is CH.sub.2CH.sub.2 or CHF. In some of these embodiments, R.sup.2 is (CH.sub.2).sub.4. In some of these embodiments, L.sup.1 is NHC(O). In some of these embodiments, R.sup.3 is

##STR00098##

optionally wherein R.sup.3 is

##STR00099##

In some of these embodiments, L.sup.2 is NHC(O). In some of these embodiments, n1 is 0; ring A has 0 double bonds and is bonded at para position, optionally wherein ring A is

##STR00100##

In some of these embodiments, n2 is 0 or 1. In some of these embodiments, each R.sup.L3a is H. In some of these embodiments, X.sup.br is N, C, or CH. In some of these embodiments: R.sup.5b is (CH.sub.2).sub.4 and R.sup.5c is absent; or R.sup.5c is (CH.sub.2).sub.4 and R.sup.5b is absent. In some of these embodiments, L.sup.5b is NHC(O). In some of these embodiments, L.sup.5c is NHC(O). In some of these embodiments, L.sup.5b is NHC(O). In some of these embodiments, n4 is 0 or 1, and R.sup.6when presentis methylene. In some of these embodiments, n5 is 0 or 1, and R.sup.7when presentis methylene. In some of these embodiments, L.sup.6-when presentis NHC(O). In some of these embodiments, L.sup.7-when presentis NHC(O). In some of these embodiments, R.sup.alb is

##STR00101##

wherein n11 is 3 and R.sup.8 is OCH.sub.3 or NO.sub.2. In some of these embodiments, R.sup.rad is DOTA or a DOTA derivative.

[0157] In some embodiments, the compound is CCZ02009, CCZ02017, CCZ02008, CCZ02025, CCZ02024, CCZ02015, CCZ02019, CCZ02012, or CCZ02013, (see Examples for chemical structures) or a salt or solvate thereof, optionally conjugated with .sup.177Lu, .sup.111In, .sup.213Bi, .sup.212Pb, .sup.47Sc, .sup.90Y, .sup.225Ac, .sup.117mSn, .sup.153Sm, .sup.149Tb, .sup.161Tb, .sup.165Er, .sup.224Ra, .sup.212Bi, .sup.227Th, .sup.223Ra, .sup.64Cu or .sup.67Cu.

[0158] In some embodiments, the compound is CCZ02009, CCZ02017, CCZ02008, CCZ02025, CCZ02024, CCZ02015, CCZ02019, CCZ02012, CCZ02005, CCZ02021, CCZ02022, CCZ02059, CCZ02060, CCZ02034, CCZ02061, or CCZ02013, (see Examples for chemical structures) or a salt or solvate thereof, optionally conjugated with .sup.177Lu, .sup.111In, .sup.213Bi, .sup.212Pb, .sup.47Sc, .sup.90Y, .sup.225Ac, .sup.117mSn, .sup.153Sm, .sup.149Tb, .sup.161Tb, .sup.165Er, .sup.224Ra, .sup.212Bi, .sup.227Th, .sup.223Ra, .sup.64Cu or .sup.67Cu.

[0159] In some embodiments, the compound is CCZ02005, CCZ02021, CCZ02022, CCZ02059, CCZ02060, CCZ02034, CCZ02061, or a salt or solvate thereof, optionally conjugated with .sup.177Lu, .sup.111In, .sup.213Bi, .sup.212Pb, .sup.47Sc, .sup.90Y, .sup.225Ac, .sup.117mSn, .sup.153Sm, .sup.149Tb, .sup.161Tb, .sup.165Er, .sup.224Ra, .sup.212Bi, .sup.227Th, .sup.223Ra, .sup.64Cu or .sup.67Cu.

[0160] When the radiometal chelator is conjugated with a therapeutic radioisotope (e.g. .sup.165Er, .sup.212Bi, .sup.166Ho, .sup.149Pm, .sup.159Gd, .sup.105Rh, .sup.109Pd, .sup.198Au, .sup.199Au, .sup.175Yb, .sup.142Pr, .sup.177Lu, .sup.111In, .sup.213Bi, .sup.212Pb, .sup.47Sc, .sup.90Y, .sup.225Ac, .sup.117mSn, .sup.153Sm, .sup.149Tb, .sup.161Tb, .sup.224Ra, .sup.227Th, .sup.223Ra, .sup.64Cu, .sup.67Cu, or the like), there is disclosed the use of certain embodiments of the compound (or a pharmaceutical composition thereof) for the treatment of PSMA-expressing conditions or diseases (e.g. tumors and the like) in a subject.

[0161] Accordingly, there is provided use of the compound in preparation of a medicament for treating a PSMA-expressing condition or disease in a subject. There is also provided a method of treating PSMA-expressing disease in a subject, in which the method comprises: administering to the subject a composition comprising the compound and a pharmaceutically acceptable excipient. For example, but without limitation, the disease may be a PSMA-expressing tumor or a PSMA-expressing cancer.

[0162] PSMA expression has been detected in various cancers (e.g. Rowe et al., 2015, Annals of Nuclear Medicine 29:877-882; Sathekge et al., 2015, Eur J Nucl Med Mol Imaging 42:1482-1483; Verburg et al., 2015, Eur J Nucl Med Mol Imaging 42:1622-1623; and Pyka et al., J Nucl Med Nov. 19, 2015 jnumed.115.164442). Accordingly, without limitation, the PSMA-expressing cancer may be prostate cancer, renal cancer, breast cancer, thyroid cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, lung cancer, liver cancer, brain tumor, melanoma, neuroendocrine tumor, ovarian cancer or sarcoma. In some embodiments, the cancer is prostate cancer.

[0163] The compounds presented herein incorporate peptides, which may be synthesized by any of a variety of methods established in the art. This includes but is not limited to liquid-phase as well as solid-phase peptide synthesis using methods employing 9-fluorenylmethoxycarbonyl (Fmoc) and/or t-butyloxycarbonyl (Boc) chemistries, and/or other synthetic approaches.

[0164] Solid-phase peptide synthesis methods and technology are well-established in the art. For example, peptides may be synthesized by sequential incorporation of the amino acid residues of interest one at a time. In such methods, peptide synthesis is typically initiated by attaching the C-terminal amino acid of the peptide of interest to a suitable resin. Prior to this, reactive side chain and alpha amino groups of the amino acids are protected from reaction by suitable protecting groups, allowing only the alpha carboxyl group to react with a functional group such as an amine group, a hydroxyl group, or an alkyl halide group on the solid support. Following coupling of the C-terminal amino acid to the support, the protecting group on the side chain and/or the alpha amino group of the amino acid is selectively removed, allowing the coupling of the next amino acid of interest. This process is repeated until the desired peptide is fully synthesized, at which point the peptide can be cleaved from the support and purified. A non-limiting example of an instrument for solid-phase peptide synthesis is the Aapptec Endeavor 90 peptide synthesizer.

[0165] To allow coupling of additional amino acids, Fmoc protecting groups may be removed from the amino acid on the solid support, e.g. under mild basic conditions, such as piperidine (20-50% v/v) in DMF. The amino acid to be added must also have been activated for coupling (e.g. at the alpha carboxylate). Non-limiting examples of activating reagents include without limitation 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP). Racemization is minimized by using triazoles, such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt). Coupling may be performed in the presence of a suitable base, such as N,N-diisopropylethylamine (DIPEA/DIEA) and the like. For long peptides or if desired, peptide synthesis and ligation may be used.

[0166] Apart from forming typical peptide bonds to elongate a peptide, peptides may be elongated in a branched fashion by attaching to side chain functional groups (e.g. carboxylic acid groups or amino groups), either: side chain to side chain; or side chain to backbone amino or carboxylate. Coupling to amino acid side chains may be performed by any known method, and may be performed on-resin or off-resin. Non-limiting examples include: forming an amide between an amino acid side chain containing a carboxyl group (e.g. Asp, D-Asp, Glu, D-Glu, and the like) and an amino acid side chain containing an amino group (e.g. Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, and the like) or the peptide N-terminus; forming an amide between an amino acid side chain containing an amino group (e.g. Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, and the like) and either an amino acid side chain containing a carboxyl group (e.g. Asp, D-Asp, Glu, D-Glu, and the like) or the peptide C-terminus; and forming a 1, 2, 3-triazole via click chemistry between an amino acid side chain containing an azide group (e.g. Lys(N.sub.3), D-Lys(N.sub.3), and the like) and an alkyne group (e.g. Pra, D-Pra, and the like). The protecting groups on the appropriate functional groups must be selectively removed before amide bond formation, whereas the reaction between an alkyne and an azido groups via the click reaction to form an 1,2,3-triazole does not require selective deprotection. Non-limiting examples of selectively removable protecting groups include 2-phenylisopropyl esters (O-2-PhiPr) (e.g. on Asp/Glu) as well as 4-methyltrityl (Mtt), allyloxycarbonyl (alloc), 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene))ethyl (Dde), and 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl (ivDde) (e.g. on Lys/Orn/Dab/Dap). O-2-PhiPr and Mtt protecting groups can be selectively deprotected under mild acidic conditions, such as 2.5% trifluoroacetic acid (TFA) in DCM. Alloc protecting groups can be selectively deprotected using tetrakis(triphenylphosphine)palladium(0) and phenyl silane in DCM. Dde and ivDde protecting groups can be selectively deprotected using 2-5% of hydrazine in DMF. Deprotected side chains of Asp/Glu (L- or D-forms) and Lys/Orn/Dab/Dap (L- or D-forms) can then be coupled, e.g. by using the coupling reaction conditions described above.

[0167] Peptide backbone amides may be N-methylated (i.e. alpha amino methylated) or N-alkylated. This may be achieved by directly using Fmoc-N-methylated amino acids (or Fmoc-N-alkylated amino acids) during peptide synthesis. Alternatively, N-methylation (or N-alkylation) under Mitsunobu conditions may be performed. First, a free primary amine group is protected using a solution of 4-nitrobenzenesulfonyl chloride (Ns-Cl) and 2,4,6-trimethylpyridine (collidine) in NMP. N-methylation may then be achieved in the presence of triphenylphosphine, diisopropyl azodicarboxylate (DIAD) and methanol. Subsequently, N-deprotection may be performed using mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in NMP. For coupling protected amino acids to N-methylated alpha amino groups, HATU, HOAt and DIEA may be used.

[0168] The PSMA-binding moiety (e.g. Lys-ureido-Glu, Lys-ureido-Aad, and the like) may be constructed on solid phase via the formation of a ureido linkage between the amino groups of two amino acids. This can be done by attaching an Fmoc-protecting amino acid (for example Fmoc-Lys(ivDde)-OH) to Wang resin using standard activation/coupling strategy (for example, Fmoc-protected amino acid (4 eq.), HATU (4 eq.) and N,N-diisopropylethylamine (7 eq.) in N,N-dimethylformamide). The Fmoc-protecting group is then removed by 20% piperidine in N,N-dimethylformamide. To form the ureido linkage, the freed amino group of the solid-phase-attached amino acid is reacted with the 2.sup.nd amino acid which has its carboxylate group protected with a t-butyl group and its amino group activated and converted to an isocyanate group (NCO). The activation and conversion of an amino group to an isocyanate group can be achieved by reacting the amino group with phosgene or triphosgene. After the formation of the ureido linkage, the side chain functional group of the amino acid (for example ivDde on Lys) can be removed, and then the linker, albumin-binding motif, and/or radiolabeling group (e.g. radiometal chelator and the like) can be subsequently coupled to the PSMA-binding moiety.

[0169] The formation of the thioether (S) linkages (e.g. for L.sup.1, L.sup.2, L.sup.3, and the like) can be achieved either on solid phase or in solution phase. For example, the formation of thioether (S) linkage can be achieved by coupling between a thiol-containing compound (such as the thiol group on cysteine side chain) and an alkyl halide (such as 3-(Fmoc-amino)propyl bromide and the like) in an appropriate solvent (such as N,N-dimethylformamide and the like) in the presence of base (such as N,N-diisopropylethylamine and the like). If the reactions are carried out in solution phase, the reactants used are preferably in equivalent molar ratio (1 to 1), and the desired products can be purified by flash column chromatography or high performance liquid chromatography (HPLC). If the reactions are carried out on solid phase, meaning one reactant has been attached to a solid phase, then the other reactant is normally used in excess amount (3 equivalents of the reactant attached to the solid phase). After the reactions, the excess unreacted reactant and reagents can be removed by sequentially washing the solid phase (resin) using a combination of solvents, such as N,N-dimethylformamide, methanol and dichloromethane, for example.

[0170] The formation of the linkage (e.g. for L.sup.1, L.sup.2, L.sup.3, and the like) between a thiol group and a maleimide group can be performed using the conditions described above for the formation of the thioether (S) linkage simply by replacing the alkyl halide with a maleimide-containing compounds. Similarly, this reaction can be conducted in solid phase or solution phase. If the reactions are carried out in solution phase, the reactants used are preferably in equivalent molar ratio (1 to 1), and the desired products can be purified by flash column chromatography or high performance liquid chromatography (HPLC). If the reactions are carried out on solid phase, meaning one reactant has been attached to a solid phase, then the other reactant is normally used in excess amount (3 equivalents of the reactant attached to the solid phase). After the reactions, the excess unreacted reactant and reagents can be removed by sequentially washing the solid phase (resin) using a combination of solvents, such as N,N-dimethylformamide, methanol and dichloromethane, for example.

[0171] Urea or thiourea linkages can be made from reaction of an amine group with an isocyanate or an isothiocyanate, respectively, which are common functional groups on radiometal chelators. The isothiocyanate functional group may be added to the radiometal chelator by reacting an amino group on the chelator with thiophosgene [i.e. C(S)Cl.sub.2]. Similarly, the isocyanate functional group may be added to the radiometal chelator by reacting an amino group on the chelator with phosgene [i.e. C(O)Cl.sub.2].

[0172] Non-peptide moieties (e.g. radiometal chelator groups, albumin-binding groups and/or linkers) may be coupled to the peptide N-terminus while the peptide is attached to the solid support. This is facile when the non-peptide moiety comprises an activated carboxylate (and protected groups if necessary) so that coupling can be performed on resin. For example, but without limitation, a bifunctional chelator, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tris(tert-butyl ester) may be activated in the presence of N-hydroxysuccinimide (NHS) and N,N-dicyclohexylcarbodiimide (DCC) for coupling to a peptide. Alternatively, a non-peptide moiety may be incorporated into the compound via a copper-catalyzed click reaction under either liquid or solid phase conditions. Copper-catalyzed click reactions are well established in the art. For example, 2-azidoacetic acid is first activated by NHS and DCC and coupled to a peptide. Then, an alkyne-containing non-peptide moiety may be clicked to the azide-containing peptide in the presence of Cu.sup.2+ and sodium ascorbate in water and organic solvent, such as acetonitrile (ACN) and DMF and the like. Non-peptide moieties may also be added in solution phase, which is routinely performed.

[0173] The synthesis of radiometal chelators is well-known and many chelators are commercially available (e.g. from Sigma-Aldrich/Milipore Sigma and others). Protocols for conjugation of radiometals to the chelators are also well known (e.g. see Examples, below).

[0174] When the peptide has been fully synthesized on the solid support, the desired peptide may be cleaved from the solid support using suitable reagents, such as TFA, triisopropylsilane (TIS) and water. Side chain protecting groups, such as Boc, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), trityl (Trt) and tert-butyl (tBu) are simultaneously removed (i.e. deprotection). The crude peptide may be precipitated and collected from the solution by adding cold ether followed by centrifugation. Purification and characterization of the peptides may be performed by standard separation techniques, such as high performance liquid chromatography (HPLC) based on the size, charge and polarity of the peptides. The identity of the purified peptides may be confirmed by mass spectrometry or other similar approaches.

[0175] The present invention will be further illustrated in the following examples.

EXAMPLES

General Methods

[0176] All chemicals and solvents were obtained from commercial sources, and used without further purification. PSMA-targeted peptides were synthesized using solid phase approach on an AAPPTec (Louisville, KY) Endeavor 90 peptide synthesizer. Purification and quality control of cold and radiolabeled peptides were performed on Agilent HPLC systems equipped with a model 1200 quaternary pump, a model 1200 UV absorbance detector (set at 220 nm), and a Bioscan (Washington, DC) NaI scintillation detector. The operation of Agilent HPLC systems was controlled using the Agilent ChemStation software. The HPLC columns used were a semi-preparative column (Luna C18, 5, 25010 mm) and an analytical column (Luna C18, 5, 2504.6 mm) purchased from Phenomenex (Torrance, CA). The HPLC solvents were A: H.sub.2O containing 0.1% TFA, and B: CH.sub.3CN containing 0.1% TFA. The collected HPLC eluates containing the desired peptide were lyophilized using a Labconco (Kansas City, MO) FreeZone 4.5 Plus freeze-drier. Mass analyses were performed using a Waters (Milford, Massachusetts) LC-MS with a QDa mass detector an ESI ion source. C18 Sep-Pak cartridges (1 cm.sup.3, 50 mg) were obtained from Waters (Milford, MA). .sup.68Ga was eluted from an iThemba Labs (Somerset West, South Africa) generator, and was purified using a DGA resin column from Eichrom Technologies LLC (Lisle, IL). Radioactivity of .sup.68Ga or .sup.177Lu-labeled peptides was measured using a Capintec (Ramsey, NJ) CRC-25R/W dose calibrator, and the radioactivity of mouse tissues collected from biodistribution studies were counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 automatic gamma counter.

General Synthesis of PSMA-Targeting Molecules

[0177] Peptidomimetic PSMA-targeting Lys-ureido-Glu moiety was synthesized by solid-phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin was swelled in CH.sub.2Cl.sub.2, followed by Fmoc removal by treating the resin with 20% piperidine in DMF. To generate the isocyanate of the H-Glu(OtBu)-OtBu moiety, a solution of H-Glu(OtBu)-OtBu and diisopropylethylamine in CH.sub.2Cl.sub.2 was cooled to 78 C. in a dry ice/acetone bath. Triphosgene was dissolved in CH.sub.2Cl.sub.2, and the resulting solution was added dropwise to the reaction at 78 C. The reaction was then allowed to warm to room temperature and stirred for 30 minutes. After which the isocyanate of the H-Glu(OtBu)-OtBu solution was added to the lysine-immobilized resin and reacted for 16 h. After washing the resin with DMF, the ivDde-protecting group was removed with 2% hydrazine in DMF. Fmoc-protected amino acids were then coupled to the side chain of Lys in presence of HATU and N,N-diisopropylethylamine. Finally, DOTA-tris(t-bu)ester (2-(4,7,10-tris(2-(t-butoxy)-2-oxoehtyl)-1,4,7,10)-tetraazacyclododecan-1-yl)acetic acid) was coupled. The peptide was then deprotected and simultaneously cleaved from the resin by treating with 95/5 trifluoroacetic acid (TFA)/triisopropylsilane (TIS) for 3-4 h at room temperature. After filtration, the peptide was precipitated by the addition of the TFA solution to cold diethyl ether. The crude peptide was purified by HPLC using the preparative column. The eluates containing the desired peptide were collected, pooled, and lyophilized.

General Synthesis of Ga or Lu-Labeled Standards

[0178] To prepare Ga or Lu-labeled standards, a solution of each precursor was incubated with GaCl.sub.3 or LuCl.sub.3 (5 eq.) in NaOAc buffer (0.1 M, 500 L, pH 4.2) at 80-90 C. for 15 min. The reaction mixture was then purified by HPLC using the semi-preparative column, and the HPLC eluates containing the desired peptide were collected, pooled, and lyophilized.

.sup.68Ga, .sup.177Lu and .sup.225Ac Radiolabeling

[0179] .sup.68Ga was eluted from a .sup.68Ge-generator with 5 mL of 0.05M HCl, collected into 2.5 mL of 12M HCl and trapped onto a DGA resin. The resin was then washed with 3 mL of 5M HCl and the purified [.sup.68Ga].sup.3+ was eluted. .sup.177Lu and .sup.225Ac were purchased from ITM (Germany). .sup.68Ga, .sup.177Lu or .sup.225Ac was added to 700 L of 2M HEPES buffer containing 15-25 nmol of peptide. The reaction mixtures were then either heated at 85-90 C. for 15-30 min or microwaved for 1 min. For .sup.68Ga and .sup.177Lu labeling, each solution was purified by semi-prep HPLC followed by C18 Sep-pak purification. A radiochemical purity of >95%, determined by analytical HPLC, was required for animal studies. For .sup.225Ac labeling, only Sep-pak purification was performed. A radiochemical purity of >95%, determined by radio-TLC, was required for animal studies.

Cell Culture and Tumour Inoculation

[0180] LNCaP cell line was obtained from ATCC (LNCaP clone FGC, CRL-1740). It was established from a metastatic site of left supraclavicular lymph node of human prostatic adenocarcinoma. Cells were cultured in PRMI 1640 medium supplemented with 10% FBS, penicillin (100 U/mL) and streptomycin (100 g/mL) at 37 C. in a humidified incubator containing 5% CO.sub.2. Cells grown to 80-90% confluence were then washed with sterile phosphate-buffered saline (1PBS pH 7.4) and trypsinization. The collected cells number was counted with a Hausser Scientific (Horsham, PA) Hemacytometer. Approximately 10 million LNCaP cells were inoculated into the left dorsal flank of immunocomprised NRG mice. The tumours were allowed to grow for 4-6 weeks and used for imaging and biodistribution studies when a volume of 200-600 mm.sup.3 was reached.

In Vitro PSMA Competitive Binding Assay and Human Serum Albumin Binding Assay

[0181] Inhibition constants (Ki) to PSMA were measured by in vitro competition binding assays using [.sup.18F]DCFPyL as the radioligand. LNCaP cells which were plated onto a 24-well poly-D-lysine coated plate for 48 h (400,000/well). Growth medium was removed and replaced with HEPES buffered saline (50 mM HEPES, pH 7.5, 0.9% sodium chloride). After 1 h, [.sup.18F]DCFPyL (0.1 nM) was added to each well (in triplicate) containing varied concentrations (0.5 mM-0.05 nM) of tested compounds The assay mixtures were incubated for 1 h at 37 C. with gentle agitation followed by two washes with cold HEPES buffered saline. A trypsin solution (0.25%, 400 L) was then added to each well to harvest the cells. Radioactivity was measured by gamma counting and Ki values calculated using the one sitefit Ki built-in model in Prism 8 (GraphPad).

[0182] Human serum albumin binding assay was performed using Transil HSA binding kit (Sovicell) according to manufacturer's recommended procedures.

PET/CT Imaging, SPECT/CT and Biodistribution

[0183] PET imaging experiments were conducted using Siemens Inveon micro PET/CT scanner. SPECT imaging experiments were conducted using an MILabs micro SPECT/CT scanner. Each tumor bearing mouse was injected 4-6 MBq of .sup.68Ga or 18.5 MBq of .sup.177Lu labeled tracer through the tail vein under anesthesia (2% isoflurane in oxygen). The mice were allowed to recover and roam freely in their cage. At pre-defined time point, the mice were sedated again with 2% isoflurane in oxygen inhalation and positioned in the scanner. A 10-min CT scan was conducted first for localization and attenuation correction after segmentation for reconstructing the PET or SPECT images. Then, a 10-min static PET imaging or a one hour (30 min2 frames) of static SPECT scan was performed to determined uptake in tumor and other organs. The mice were kept warm by a heating pad during acquisition.

[0184] For biodistribution studies, the mice were injected with the radiotracer as described above. The mice were anesthetized with 2% isoflurane inhalation, and euthanized by CO.sub.2 inhalation. Blood was withdrawn immediately from the heart, and the organs/tissues of interest were collected. The collected organs/tissues were weighed and counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 gamma counter. The uptake in each organ/tissue was normalized to the injected dose (radioactivity) using a standard curve, and expressed as the percentage of the injected dose per gram of tissue (% ID/g).

Example 1: Synthesis and Evaluation of Ccz02009 in Comparison to HTK03170 without a Gly Spacer

[0185] The chemical structure of CCZ02009 is below:

##STR00102##

[0186] The synthesis of CCZ02009 follows the general synthesis procedures as described above except that CCZ02009 is based on the Lys-ureido-Aad moiety. To generate the isocyanate of the 2-aminoadipyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tertbutyl ester hydrochloride and diisopropylethylamine in CH.sub.2Cl.sub.2 was cooled to 78 C. in a dry ice/acetone bath. Triphosgene was dissolved in CH.sub.2Cl.sub.2, and the resulting solution was added dropwise to the reaction at 78 C. The reaction was then allowed to warm to room temperature and stirred for 30 minutes to give a solution of the isocyanate of the 2-aminoadipyl moiety. Following the urea formation and ivDde deprotection on the Lys side chain, Fmoc-Ala(9-anth)-OH, Fmoc-Tranexamic acid, Fmoc-Gly-OH, Fmoc-Lys(ivDde)-OH, Fmoc-Gly-OH and 4-(p-methoxyphenyl)butyric acid were coupled sequentially. Subsequently, the ivDde group was deprotected and finally DOTA-tris(t-bu)ester was coupled. CCZ02009 was then purified by HPLC. Mass calculated [M+2H].sup.2+=762.9, found 763.0.

[0187] The chemical structure of HTK03170 is shown below:

##STR00103##

[0188] As a comparison, HTK03170 was synthesized, which lacks a glycine spacer between the PSMA and albumin binding moieties shown in CCZ02009. Mass calculated [M+2H].sup.2+=734.4, found 734.7.

[0189] Table 3 shows that with a Gly spacer between the PSMA and albumin binding moieties, PSMA binding affinity increased from 1.530.33 to 0.120.02 nM, and albumin binding affinity increased from 70.13.2 to 64.92.2 M. FIG. 2A shows the representative binding affinity curves for CCZ02009 (left panel) and HTK03170 (right panel). FIG. 2B and Table 4 show the PET imaging and biodistribution results using .sup.68Ga-CCZ02009 in NRG-mice bearing LNCaP tumors 1 h (FIG. 2B left panel) and 3 h (FIG. 2B right panel) post-injection (p.i.). Overall high and sustained blood radioactivity was observed at both timepoints, indicating the strong albumin binding of CCZ02009.

TABLE-US-00003 TABLE 3 PSMA and human albumin binding affinities for CCZ02009 and HTK03170 (n = 3). PSMA binding affinity Human albumin binding affinity (Ki, nM) (Kd, M) CCZ02009 0.12 0.02 64.9 2.2 HTK03170 1.53 0.33 70.1 3.2

TABLE-US-00004 TABLE 4 Biodistribution results in NRG-mice bearing LNCaP tumors administered with .sup.68Ga-CCZ02009 at 1 and 3 h p.i. Values are in percent injected dose per gram of tissue (% ID/g). 1 h p.i. 3 h p.i. (n = 4) (n = 4) .sup.68Ga-CCZ02009 Avg Std Avg Std Blood 19.52 4.03 19.18 2.33 Urine 63.67 19.48 56.09 42.58 Fat 1.35 0.14 1.52 0.52 Seminal gland 0.88 0.13 1.73 1.04 Testes 2.33 0.48 2.28 0.83 Intestine 1.72 0.41 1.53 0.28 Spleen 1.56 0.12 2.17 0.93 Pancreas 1.56 0.36 1.41 1.03 Stomach 0.71 0.25 0.73 0.23 Liver 3.04 0.49 3.35 0.83 Adrenal gland 3.82 1.77 4.34 1.50 kidney 7.57 2.09 9.28 2.06 Heart 4.02 0.91 3.76 0.36 Lungs 6.51 0.71 7.15 1.78 LNCaP tumor 7.11 0.95 17.69 4.44 Bone 0.77 0.13 1.62 0.61 Muscle 1.15 0.11 1.34 0.27 Brain 0.30 0.08 0.32 0.08 Salivary gland 2.74 0.52 3.82 1.16 Thyroid 2.92 0.51 3.59 0.73

Example 2: Synthesis and Evaluation of CCZ02060 and CCZ02059 with Additional Gly Spacers

[0190] The chemical structures of CCZ02060 and CCZ02059 are shown below:

##STR00104## ##STR00105##

[0191] The synthesis of CCZ02060 and CCZ02059 follows the synthesis procedures of CCZ02009 as described above, except that CCZ02060 contains two Gly spacers and CCZ02059 contains four Gly spacers. For CCZ02060, mass calculated [M+2H].sup.2+=791.4, found 791.5. For CCZ02059, mass calculated [M+2H].sup.2+=848.4, found 848.5.

[0192] CCZ02060 and CCZ02059 binds to PSMA with affinities (Ki) of 1.090.19 nM and 10.843.28 nM (n=2), respectively. FIG. 3 shows the representative binding affinity curves for CCZ02060 (left panel) and CCZ02059 (right panel). The number of Gly spacers has an impact on the PSMA binding affinity, i.e. the most favorable binding affinity was observed with a single Gly spacer (CCZ02009), followed by two Gly spacers (CCZ02060) and four Gly spacers (CCZ02059).

Example 3: Synthesis and Evaluation of CCZ02017 in Comparison to HTK03170 without a Gly Spacer

[0193] The chemical structure of CCZ02017 is shown below:

##STR00106##

[0194] The synthesis of CCZ02017 follows the synthesis procedures of CCZ02009 as described above, except for the albumin binder, which is 4-(p-nitrophenyl)butyric acid in CCZ02017. The 4-(p-nitrophenyl)butyric acid is substantially weaker than 4-(p-methoxyphenyl)butyric acid (Ref. Kuo et al. J Nucl Med. 2021 April; 62(4):521-527). FIG. 4 shows SPECT/CT images of .sup.177Lu-CCZ02017 in NRG-mice bearing LNCaP tumors at 3, 24, 72, 144 and 240 h p.i. Table 5 shows the biodistribution of .sup.177Lu-CCZ02017 in NRG-mice bearing LNCaP tumors at 3, 24, 72, 144 and 240 h p.i. In comparison, .sup.177Lu-HTK03170 shows similar blood % ID/g values (Table 4) to .sup.177Lu-CCZ02017 at 24 and 72 h p.i. (see Table 6). Since CCZ02017 has a weaker albumin binder, the data indicates that the introduction of a Gly spacer improves albumin binding. The LNCaP tumor uptake in .sup.177Lu-CCZ02017 is substantially improved compared to .sup.177Lu-HTK03170.

TABLE-US-00005 TABLE 5 Biodistribution results in NRG-mice bearing LNCaP tumors administered with .sup.177Lu-CCZ02017 at 3, 24, 72, 144 and 240 h p.i. Values are in % ID/g. 3 h p.i. 24 h p.i. 72 h p.i. 144 h p.i. 240 h p.i. .sup.177Lu- (n = 5) (n = 5) (n = 5) (n = 5) (n = 5) CCZ02017 Avg Std Avg Std Avg Sto Avg Std Avg Std Blood 14.17 0.60 0.61 0.02 0.07 0.03 0.01 0.00 0.00 0.00 Urine 97.91 47.95 9.85 3.59 2.63 0.98 1.88 0.85 0.43 0.24 Fat 1.85 0.24 0.20 0.05 0.15 0.04 0.22 0.13 0.06 0.03 Seminal 0.93 0.13 0.07 0.02 0.03 0.00 0.01 0.01 0.00 0.00 gland Testes 6.56 7.05 0.48 0.07 0.29 0.03 0.15 0.03 0.08 0.01 Intestine 1.03 0.56 0.13 0.02 0.04 0.01 0.01 0.00 0.01 0.00 Spleen 2.25 1.09 0.35 0.07 0.38 0.08 0.37 0.17 0.50 0.51 Pancreas 2.27 1.61 0.11 0.02 0.04 0.01 0.01 0.01 0.00 0.00 Stomach 1.55 1.84 0.15 0.02 0.04 0.02 0.02 0.02 0.01 0.01 Liver 2.31 1.13 0.31 0.04 0.23 0.11 0.09 0.02 0.06 0.05 Adrenal 3.41 0.69 0.61 0.08 0.34 0.12 0.23 0.08 0.02 0.02 gland kidney 17.31 1.01 5.58 0.59 3.21 0.84 1.98 0.61 0.46 0.09 Heart 3.24 0.24 0.24 0.07 0.10 0.02 0.04 0.02 0.01 0.01 Lungs 6.68 0.69 0.55 0.03 0.16 0.03 0.08 0.03 0.14 0.27 LNCaP 39.27 8.72 89.90 30.12 70.84 21.79 116.43 43.13 95.45 15.98 tumor Bone 0.78 0.13 0.07 0.03 0.02 0.00 0.02 0.02 0.01 0.02 Muscle 1.18 0.08 0.08 0.01 0.02 0.01 0.01 0.01 0.01 0.02 Brain 0.24 0.02 0.03 0.00 0.01 0.00 0.01 0.00 0.00 0.00 Salivary 2.43 0.85 0.35 0.03 0.14 0.03 0.05 0.03 0.01 0.01 gland Thyroid 2.87 0.18 0.40 0.05 0.16 0.09 0.11 0.02 0.03 0.00 Lacrimal 0.20 0.06 0.04 0.06 0.01 0.02 0.00 0.00 0.00 0.00 gland

TABLE-US-00006 TABLE 6 Biodistribution results in NRG-mice bearing LNCaP tumors administered with .sup.177Lu-HTK03170 at 24 and 72 h p.i. Values are in % ID/g. 24 h p.i. 72 h p.i. (n = 5) (n = 5) .sup.177Lu-HTK03170 Avg Std Avg Std Blood 0.73 0.21 0.07 0.01 Urine 19.02 13.28 4.96 1.96 Intestine 0.18 0.05 0.08 0.04 Spleen 0.33 0.07 0.36 0.12 Liver 0.49 0.05 0.27 0.02 kidney 6.06 0.91 4.30 0.84 LNCaP tumor 42.96 6.66 56.98 5.98 Bone 0.18 0.11 0.19 0.08 Muscle 0.10 0.01 0.15 0.07 Salivary gland 0.35 0.08 0.31 0.09

TABLE-US-00007 TABLE 7 Biodistribution results in NRG-mice bearing LNCaP tumors administered with .sup.225Ac-CCZ02017 at 3, 24, 72, 144 and 240 h p.i. Values are in % ID/g. 3 h p.i. 24 h p.i. 72 h p.i. 144 h p.i. 240 h p.i. (n = 5) (n = 5) (n = 5) (n = 5) (n = 5) .sup.225Ac-CCZ02017 Avg Std Avg Std Avg Std Avg Std Avg Std Blood 9.83 1.34 0.28 0.16 0.01 0.01 0.01 0.01 0.02 0.02 Urine 142.80 26.10 4.30 3.43 1.33 1.30 0.55 0.73 0.41 0.50 Fat 1.96 0.60 0.13 0.02 0.40 0.63 0.07 0.01 0.13 0.05 Seminal gland 2.26 3.64 0.15 0.15 0.03 0.02 0.04 0.01 0.06 0.02 Testes 2.73 0.62 0.38 0.14 0.33 0.18 0.29 0.11 0.27 0.04 Intestine 1.02 0.13 0.15 0.08 0.06 0.02 0.06 0.04 0.06 0.02 Spleen 1.15 0.49 0.50 0.14 0.93 0.87 0.65 0.24 1.14 0.40 Pancreas 1.14 0.10 0.09 0.01 0.09 0.04 0.14 0.18 0.06 0.02 Stomach 0.47 0.12 0.20 0.13 0.06 0.03 0.05 0.03 0.08 0.03 Liver 1.90 0.12 0.68 0.16 0.51 0.26 0.71 0.12 1.49 0.33 Adrenal gland 3.61 1.96 0.59 0.24 24.11 49.82 0.31 0.24 0.53 0.21 kidney 14.29 2.18 6.87 2.16 3.62 0.56 1.95 0.43 2.24 0.65 Heart 2.27 0.10 0.25 0.08 0.16 0.05 0.14 0.06 0.16 0.06 Lungs 4.93 0.63 0.58 0.13 0.19 0.04 0.13 0.05 0.18 0.03 LNCaP tumor 23.63 2.08 42.31 9.38 54.12 15.76 71.25 8.78 123.67 15.35 Bone 1.24 0.74 0.30 0.10 0.34 0.11 0.23 0.04 0.57 0.17 Muscle 0.80 0.12 0.06 0.02 0.04 0.01 0.02 0.01 0.08 0.09 Brain 0.19 0.03 0.03 0.02 0.02 0.01 0.02 0.00 0.02 0.01 Salivary gland 3.37 0.99 0.35 0.12 0.33 0.19 0.21 0.06 0.32 0.28 Thyroid 1.72 0.78 0.33 0.10 0.22 0.10 0.23 0.06 0.23 0.12 Lacrimal gland 0.92 0.29 0.32 0.24 1.39 1.76 0.65 0.58 0.19 0.30

Example 4: Synthesis and Evaluation of CCZ02008

[0195] The chemical structure of CCZ02008 is shown below:

##STR00107##

[0196] The synthesis of CCZ02008 follows the synthesis procedures of CCZ02009 as described above, and instead of Aad, it incorporates 4R-F-Glu. Mass calculated [M+2H].sup.2+=764.9, found 765.2. CCZ02008 binds to PSMA with high affinity Ki=0.480.1 nM (n=3). See FIG. 5 and Table 8.

TABLE-US-00008 TABLE 8 Biodistribution results in NRG-mice bearing LNCaP tumors administered with .sup.177Lu-CCZ02008 at 4, 24, 72 and 120 h p.i. Values are in % ID/g. 4 h p.i. 24 h p.i. 72 h p.i. 120 h p.i. .sup.177Lu- (n = 5) (n = 5) (n = 5) (n = 5) CCZ02008 Avg Std Avg Std Avg Std Avg Std Blood 24.97 1.63 4.37 0.93 0.42 0.20 0.14 0.03 Urine 76.61 24.30 28.57 11.80 4.51 2.97 3.80 2.05 Fat 2.63 0.55 0.71 0.15 0.39 0.17 0.22 0.06 Seminal gland 1.53 0.53 0.38 0.11 0.15 0.05 0.27 0.32 Testes 3.83 0.51 1.86 0.29 0.92 0.16 0.67 0.03 Intestine 1.87 0.11 0.59 0.11 0.15 0.06 0.14 0.04 Spleen 2.15 0.20 0.86 0.22 0.83 0.31 1.45 0.34 Pancreas 2.20 0.25 0.62 0.10 0.17 0.06 0.11 0.02 Stomach 1.11 0.05 0.48 0.13 0.18 0.12 0.37 0.20 Liver 4.26 0.43 1.16 0.16 0.47 0.13 0.30 0.07 Adrenal gland 5.91 2.67 2.39 0.60 2.59 0.98 1.39 0.64 kidney 10.56 1.95 7.55 1.46 3.53 1.13 2.04 0.69 Heart 5.42 0.45 1.27 0.21 0.37 0.07 0.22 0.02 Lungs 10.19 1.59 2.49 0.57 0.69 0.19 0.30 0.05 LNCaP tumor 21.30 1.74 38.57 5.32 38.46 4.17 45.01 6.28 Bone 1.49 0.20 0.36 0.09 0.26 0.18 0.14 0.11 Muscle 1.75 0.18 0.40 0.09 0.11 0.08 0.09 0.09 Brain 0.47 0.05 0.09 0.02 0.03 0.02 0.02 0.01 Salivary gland 4.23 0.39 1.38 0.29 0.55 0.29 0.34 0.13 Thyroid 4.29 0.40 1.54 0.31 0.65 0.26 0.39 0.07 Lacrimal gland 1.44 0.98 0.12 0.08 0.07 0.04 0.12 0.09

Example 5: Synthesis and Evaluation of CCZ02025

[0197] The chemical structure of CCZ02025 is shown below:

##STR00108##

[0198] The synthesis of CCZ02025 follows the synthesis procedures of CCZ02009 as described above, instead of Aad, it incorporates 4R-F-Glu, and instead of 4-(p-methoxyphenyl)butyric acid, it incorporates 4-(p-nitrophenyl)butyric acid. Mass calculated [M+2H].sup.2+=772.4, found 772.6. CCZ02025 binds to PSMA with high affinity Ki=0.59 nM (FIG. 6, n=1), and .sup.68Ga-CCZ02025 shows good tumor uptake and overall background tissue clearance (Table 9).

TABLE-US-00009 TABLE 9 Biodistribution results in NRG-mice bearing LNCaP tumors administered with .sup.68Ga-CCZ02025 at 1 and 3 h p.i. Values are in % ID/g. 1 h p.i. 3 h p.i. (n = 4) (n = 4) .sup.68Ga-CCZ02025 Avg Std Avg Std Blood 19.40 1.41 13.83 0.35 Urine 104.40 66.50 101.55 41.69 Fat 2.74 0.99 1.79 0.87 Seminal gland 2.55 2.65 1.83 1.91 Testes 2.65 0.35 2.80 0.34 Intestine 1.93 0.12 1.12 0.20 Spleen 1.90 0.31 1.17 0.18 Pancreas 1.89 0.19 1.13 0.13 Stomach 0.59 0.09 0.57 0.10 Liver 4.07 1.19 3.21 0.72 Adrenal gland 5.96 2.10 4.26 3.79 kidney 14.01 2.96 9.90 1.05 Heart 4.13 0.49 2.86 0.93 Lungs 8.79 0.98 5.21 0.60 LNCaP tumor 9.19 0.77 18.79 2.25 Bone 1.01 0.32 1.27 0.35 Muscle 1.48 0.11 0.95 0.06 Brain 0.30 0.04 0.22 0.02 Salivary gland 3.24 0.77 2.47 0.20 Thyroid 4.11 0.48 2.41 0.14

Example 6: Synthesis and Evaluation of CCZ02024

##STR00109##

[0199] The synthesis of CCZ02024 follows the synthesis procedures of CCZ02025 as described above, instead of 4R-F-Glu, it incorporates Glu. Mass calculated [M+2H].sup.2+=763.4, found 763.8. CCZ02024 binds to PSMA with high affinity Ki=1.54 nM (FIG. 7, n=1).

Example 7: Synthesis and Evaluation of CCZ02015

[0200] The chemical structure of CCZ02015 is shown below:

##STR00110##

[0201] The synthesis of CCZ02015 follows the synthesis procedures of CCZ02009 as described above. The differences are that CCZ02015 does not contain the Gly spacer and incorporate an elongated linker, i.e. beta-homoLys instead of Lys. Mass calculated [M+2H].sup.2+=741.4, found 741.5. CCZ02015 binds to PSMA with high affinity Ki=1.090.30 nM (FIG. 8, n=3), and .sup.68Ga-CCZ02015 shows good tumor uptake and overall background tissue clearance (Table 10).

TABLE-US-00010 TABLE 10 Biodistribution results in NRG-mice bearing LNCaP tumors administered with .sup.68Ga-CCZ02015 at 1 and 3 h p.i. Values are in % ID/g. 1 h p.i. 3 h p.i. (n = 4) (n = 4) .sup.68Ga-CCZ02015 Avg Std Avg Std Blood 15.78 1.94 10.81 1.66 Urine 177.03 117.95 84.38 38.68 Fat 1.52 0.68 1.04 0.75 Seminal gland 0.72 0.17 1.63 1.36 Testes 1.77 0.25 2.07 1.33 Intestine 1.46 0.29 1.17 0.29 Spleen 1.28 0.24 1.01 0.28 Pancreas 1.34 0.20 1.10 0.29 Stomach 0.46 0.15 0.84 0.87 Liver 2.98 1.03 2.13 0.83 Adrenal gland 3.28 1.82 3.36 2.05 kidney 11.93 2.31 10.94 3.35 Heart 3.19 0.46 2.55 0.61 Lungs 5.90 1.37 4.65 1.25 LNCaP tumor 11.16 1.47 22.60 3.64 Bone 0.92 0.58 1.20 0.61 Muscle 1.07 0.12 1.13 0.60 Brain 0.25 0.04 0.19 0.06 Salivary gland 2.19 0.28 2.18 0.45 Thyroid 2.54 0.22 2.09 0.73

Example 8: Synthesis and Evaluation of CCZ02019

[0202] The chemical structure of CCZ02019 is shown below:

##STR00111##

[0203] The synthesis of CCZ02019 follows the synthesis procedures of CCZ02015 as described above. The difference is that CCZ02019 incorporates 4R-F-Glu instead of Aad in the PSMA binding motif. Mass calculated [M+2H].sup.2+=743.4, found 743.7. .sup.177Lu-CCZ02019 shows good tumor uptake and overall background tissue clearance (Table 11).

TABLE-US-00011 TABLE 11 Biodistribution results in NRG-mice bearing LNCaP tumors administered with .sup.177Lu-CCZ02019 at 3, 24, 72, 144 and 240 h p.i. Values are in % ID/g. 3 h p.i. 24 h p.i. 72 h p.i. 144 h p.i. 240 h p.i. (n = 4) (n = 4) (n = 4) (n = 4) (n = 5) .sup.177Lu-CCZ02019 Avg Std Avg Std Avg Std Avg Std Avg Std Blood 11.22 1.88 0.70 0.21 0.13 0.07 0.04 0.02 0.01 0.00 Urine 180.95 58.73 8.42 1.26 1.12 0.47 0.84 0.48 0.37 0.30 Fat 1.91 0.79 0.33 0.15 0.16 0.03 0.11 0.01 0.06 0.04 Seminal gland 0.59 0.13 0.23 0.25 0.06 0.02 0.03 0.01 0.01 0.01 Testes 2.55 0.41 0.37 0.22 0.39 0.06 0.33 0.05 0.16 0.05 Intestine 0.98 0.22 0.23 0.06 0.08 0.03 0.03 0.00 0.02 0.00 Spleen 1.53 0.62 0.37 0.08 0.45 0.17 0.51 0.08 0.46 0.34 Pancreas 1.07 0.19 0.17 0.04 0.09 0.02 0.06 0.01 0.03 0.01 Stomach 0.58 0.42 0.73 0.71 0.15 0.13 0.03 0.01 0.02 0.00 Liver 2.18 0.49 0.48 0.15 0.29 0.08 0.19 0.02 0.15 0.09 Adrenal gland 2.79 0.56 0.54 0.21 0.53 0.16 0.31 0.05 0.11 0.03 kidney 10.42 1.01 4.02 0.88 1.84 0.68 1.10 0.20 0.52 0.22 Heart 2.52 0.49 0.37 0.07 0.18 0.04 0.13 0.02 0.05 0.02 Lungs 5.22 1.25 0.65 0.36 0.41 0.20 0.93 1.47 0.09 0.04 LNCaP tumor 50.23 13.43 55.39 5.20 45.10 12.28 40.77 14.92 25.30 15.24 Bone 1.03 0.77 0.18 0.03 0.05 0.03 0.04 0.04 0.00 0.01 Muscle 0.87 0.18 0.11 0.04 0.04 0.02 0.03 0.01 0.01 0.01 Brain 0.18 0.04 0.03 0.00 0.01 0.00 0.01 0.00 0.00 0.00 Salivary gland 1.92 0.20 0.56 0.18 0.27 0.05 0.34 0.28 0.10 0.05 Thyroid 2.44 0.50 0.52 0.06 0.37 0.04 0.28 0.10 0.12 0.04 Lacrimal gland 0.39 0.22 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

Example 9: Synthesis and Evaluation of CCZ02012 and CCZ02013

[0204] The chemical structure of CCZ02012 (left) and CCZ02013 (right) are shown below:

##STR00112##

[0205] The synthesis of CCZ02012 and CCZ02013 follows the general synthesis procedures as described above on the Lys-ureido-Aad backbone, and instead of Fmoc-Tranexamic acid, Fmoc-trans-4-aminocyclohexane carboxylic acid (ACHC) and Fmoc-cis-4-ACHC were incorporated, respectively. For CCZ02012, mass calculated [M+2H].sup.2+=546.8, found 547.1. For CCZ02013, mass calculated [M+2H].sup.2+=546.8, found 547.2. The use of ACHC, either trans or cis, did not affect the binding to PSMA substantially. CCZ02012 and CCZ02013 bind to PSMA at Ki=1.67 nM (n=1) and Ki=1.530.21 nM (n=2), respectively. FIG. 9 shows the binding assay curves for CCZ02012 (9A) and CCZ02013 (9B).

Example 10: Synthesis and Evaluation of CCZ02021 and CCZ02022

[0206] The chemical structures of CCZ02021 and CCZ02022 are shown below:

##STR00113##

[0207] The synthesis of CCZ02021 and CCZ02022 follows the synthesis procedures of CCZ02012 as described with CCZ02021 incorporating a Gly spacer, and CCZ02022 incorporating a Gly spacer and beta-homoLys instead of Lys. For CCZ02021, mass calculated [M+2H].sup.2+=763.4, found 763.5. For CCZ02022, mass calculated [M+2H].sup.2+=770.4, found 770.7. CCZ02021 and CCZ02022 bind to PSMA at Ki=5.71 nM (n=1) and Ki=11.2 nM (n=1), respectively. FIG. 9 shows the binding assay curves for CCZ02021 (10A) and CCZ02022 (10B).

Example 11: Synthesis and Evaluation of CCZ02034

[0208] The chemical structure of CCZ02034 is shown below:

##STR00114##

[0209] The synthesis of CCZ02034 follows the synthesis procedures of CCZ02017 as described with CCZ02034 incorporating a crown chelator instead of DOTA. Mass calculated [M+2H].sup.2+=814.4, found 814.6. CCZ02034 binds to PSMA at Ki=2.82 nM (n=1). See FIG. 11.

Example 12: Synthesis and Evaluation of CCZ02005

[0210] The chemical structure of CCZ02005 is shown below:

##STR00115##

[0211] The synthesis of CCZ02005 follows the general procedures as described above with a PEG.sub.2 spacer incorporated between the albumin binding group and the DOTA chelator. Mass calculated [M+2H].sup.2+=806.9, found 807.0. CCZ02005 binds to PSMA at Ki=2.08 nM (n=1). See FIG. 12. The binding affinity is comparable to HTK03170, indicating that adding a spacer between the albumin binder and the chelator does not substantially impact the binding affinity to PSMA.

Example 13: Synthesis and Evaluation of CCZ02061

[0212] The chemical structure of CCZ02061 is shown below:

##STR00116##

[0213] The synthesis of CCZ02061 follows the synthesis procedures of CCZ02017 described above with addition of a Gly spacer incorporated between the albumin binding group and the DOTA chelator. Mass calculated [M+2H].sup.2+=798.9, found 798.9. CCZ02017 binds to PSMA at Ki=1.140.37 nM (n=2). See FIG. 13. The present invention has been described with regard to one or more embodiments. However, it will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the following claims. The scope of the invention should therefore not be limited by the preferred embodiments set forth in the above Examples, but should be given the broadest interpretation consistent with the description as a whole.