PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) LIGANDS WITH IMPROVED TISSUE SPECIFICITY

Abstract

The present invention relates to a compound of formula (1), and to a complex comprising said compound and a radionuclide, and to the respective pharmaceutical composition, the compound having the following structure

##STR00001##

or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is H or —CH.sub.3, preferably H, wherein R.sup.2, R.sup.3 and R.sup.4 are independently of each other, selected from the group consisting of —CO.sub.2H, —SO.sub.2H, —SO.sub.3H, —OSO.sub.3H, —PO.sub.2H, —PO.sub.3H and —OPO.sub.3H.sub.2, Q.sup.1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl, Q.sup.2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, A is a chelator residue derived from a chelator selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (=DOTA), N,N″-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N″-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid, (NODAGA), 2-(4,7, 10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA), 1,4,7-riazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid](NOPO), 3,6,9, 15-tetraazabicyclo[9.3.1.]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N′-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), Diethylenetriaminepentaacetic acid (DTPA), Trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7, 10-triazacyclododecane-4,7, 10-triacetic acid (oxo-Do3A) p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1 B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1 M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA), X.sup.1, X.sup.2, Y.sup.1, Y.sup.2, Z.sup.1 and Z.sup.2, are independently of each other, charged amino acids, q is an integer of from 0-3, n, m and p, are independently of each other an integer of from 0 to 9, n1, n2, m1, m2, p1, p2, are independently of ach other, an integer of from 0 to 3, and wherein n1+n2>0, m1+m2>0 and p1+p2>0, and wherein n+m+p>0. Further, the present invention relates to the compound, the complex, and the pharmaceutical composition for use in treating, ameliorating or preventing PSMA-expressing cancers, in particular prostate cancer, and/or metastases thereof.

Claims

1. A compound of formula (1) ##STR00055## or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is H or —CH.sub.3, preferably H, wherein R.sup.2, R.sup.3 and R.sup.4 are independently of each other, selected from the group consisting of —CO.sub.2H, —SO.sub.2H, —SO.sub.3H, —OSO.sub.3H, —PO.sub.2H, —PO.sub.3H and —OPO.sub.3H.sub.2, Q.sup.1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl, Q.sup.2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, A is a chelator residue derived from a chelator selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (=DOTA), N,N″-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N″-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid, (NODAGA), 2-(4,7, 10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA), 1,4,7-riazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9, 15-tetraazabicyclo[9.3.1.]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (=PCTA), N′-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), Diethylenetriaminepentaacetic acid (DTPA), Trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7, 10-triazacyclododecane-4,7, 10-triacetic acid (oxo-Do3A) p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1 B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1 M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA), X.sup.1, X.sup.2, Y.sup.1, Y.sup.2, Z.sup.1 and Z.sup.2, are independently of each other, charged amino acids, q is an integer of from 0-3, n, m and p, are independently of each other an integer of from 0 to 9, n1, n2, m1, m2, p1, p2, are independently of ach other, an integer of from 0 to 3, and wherein n1+n2>0, m1+m2>0 and p1+p2>0, and wherein n+m+p>0.

2. The compound of claim 1, wherein A is a chelator residue having a structure selected from the group consisting of ##STR00056##

3. The compound of claim 1, wherein (n1+n2)n+(m1+m2)m+(p1+p2)p is at least 2.

4. The compound of claim 1, wherein (n1+n2)n+(m1+m2)m+(p1+p2)p is an integer of from 2 to 20, preferably of from 2 to 10, more preferably of from 4 to 8, more preferably 6.

5. The compound of claim 1, wherein Q.sup.1 preferably comprises a residue selected from the group consisting of naphtyl, phenyl, biphenyl, indolyl, benzothiazolyl, naphtylmethyl, phenylmethyl, biphenylmethyl, indolylmethyl and benzothiazolylmethyl, more preferably wherein Q.sup.1 is selected from the group consisting of ##STR00057## preferably wherein Q.sup.1 is ##STR00058##

6. The compound of claim 1, wherein R.sup.3, R.sup.2 and R.sup.4 are —CO.sub.2H and R.sup.1 is H.

7. The compound of claim 1, wherein Q.sup.2 is ##STR00059## preferably ##STR00060##

8. The compound of claim 1, wherein X.sup.1, X.sup.2, Y.sup.1, Y.sup.2, Z.sup.1 and Z.sup.2, are independently of each other, at physiological pH, positively or negatively charged amino acids, and wherein the positively charged amino acids are, independently of each other, selected from the group consisting of arginine, lysine, histidine homoarginine, 3- and 4-substituted arginine analogs, N(delta)-methyl-arginine (deltaMA), canavanine, substituted analogs of canavanine, α-Amino-β-guanidinopropionic acid, γ-guanidinobutyric acid, citrulline, 3-guanidinopropionic acid, 4-{[amino(imino)methyl]amino}butanoic acid, 6-{[amino(imino)methyl]amino}hexanoic acid, 2-Amino-3-guanidinopropionic acid, Arginine hydroxamate, Agmatine (CAS #: 2482-00-0), and NG-Methyl-arginine, preferably, the basic amino acids are, independently of each other, selected from the group consisting of lysine (K), histidine (H) and arginine (R).

9. The compound of claim 1, wherein X.sup.1, X.sup.2, Y.sup.1, Y.sup.2, Z.sup.1 and Z.sup.2, are independently of each other, at physiological pH, positively or negatively charged amino acids, and wherein the negatively charged amino acids are, independently of each other, selected from the group consisting of homoglutamic acid, a sulfonic acid derivative of Cys, cysteic acid, homocysteic acid, aspartic acid (D), glutamic acid (E), preferably, the acidic amino acids are, independently of each other, selected from aspartic acid and glutamic acid.

10. Complex comprising (a) a radionuclide, and (b) the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

11. The complex of claim 10, wherein, the radionuclide is selected from the group consisting .sup.889Zr, .sup.44Sc, .sup.111In, .sup.90Y, .sup.66Ga, .sup.67Ga, .sup.68Ga, .sup.177Lu, .sup.99mTc, .sup.60Cu, .sup.61Cu, .sup.62Cu, .sup.64Cu, .sup.66Cu, .sup.67Cu, .sup.149Tb, .sup.152Tb, .sup.155Tb, .sup.153Sm, .sup.161Tb, .sup.153Gd, .sup.155Gd, .sup.157Gd, .sup.213Bi, .sup.225Ac, .sup.230U, .sup.223Ra, .sup.165Er, .sup.52Fe, .sup.59Fe, and radionuclides of Pb (such as .sup.203Pb and .sup.212Pb, .sup.211Pb, .sup.213Pb, .sup.214Pb, .sup.209Pb, .sup.198Pb, .sup.197Pb).

12. A pharmaceutical composition comprising a compound of claim 1.

13. A method for treating or preventing PSMA-expressing cancer and/or metastases thereof, in particular prostate cancer and/or metastases thereof with a compound of claim 1.

14. A method for diagnosing PSMA-expressing cancer and/or metastases thereof, in particular prostate cancer and/or metastases thereof with a compound of claim 1.

15. (canceled)

Description

FIGURES

[0217] FIG. 1: Pharmacokinetic study with small-animal PET imaging. Time activity curves for kidney after injection of 0.5 nmol .sup.68Ga-labeled compounds in LNCaP-tumor-bearing athymic nude mice (right trunk) up to 60 min p.i. SUV=standardized uptake value.

[0218] FIGS. 2.1-2.10: Pharmacokinetic study with small-animal PET imaging. Time activity curves for tumor and muscle after injection of 0.5 nmol of the respective .sup.68Ga-labeled compound X (see Table 5) in LNCaP-tumor-bearing athymic nude mice (right trunk) up to 60 min p.i. SUV=standardized uptake value.

[0219] FIGS. 3.1-3.10: Small-animal PET imaging study. Whole-body maximum intensity projection of 0.5 nmol of the respective .sup.68Ga-labeled compound X (see Table 6) in LNCaP-tumor-bearing athymic nude mice (right trunk) 60 min p.i. (FIG. X A) and 120 min p.i. (FIG. X B) obtained from small animal PET imaging.

[0220] The following examples shall merely illustrate the invention. Whatsoever, they shall not be construed as limiting the scope of the invention.

EXAMPLES

[0221] All commercially available chemicals were of analytical grade and used without further purification. [.sup.68Ga]GaCl.sub.4.sup.− was obtained from a .sup.68Ge/.sup.68Ga generator (Eckert&Ziegler). [.sup.177Lu]LuCl.sub.3 was obtained from ITG. The compounds were analyzed using reversed-phase high performance liquid chromatography (RP-HPLC; Chromolith RP-18e, 100×4.6 mm; Merck, Darmstadt, Germany). Analytical HPLC runs were performed using a linear gradient 5% (A) (0.1% aqueous TFA) to 50% B (0.1% TFA in CH.sub.3CN)) in 24 min at 1 mL/min.

[0222] Analytical HPLC runs were performed using the system Agilent 1200 series (Agilent Technologies, Santa Clara, Calif., USA). UV absorbance was measured at 220 and 280 nm, respectively. For mass spectrometry a LC-MS SQ300 (Perkin Elmer, Waltham, Mass., USA) was used.

[0223] The precursors PSMA-617 (2-[3-(1-Carboxy-5-{3-naphthalen-2-yl-2-[(4-{[2-(4,7,10-tris-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl)-acetylamino]-methyl}-cyclohexanecarbonyl)-amino]-propionylamino}-pentyl)-ureido]-pentanedioic acid) and PSMA-10 ([Glu-urea-Lys(Ahx)].sub.2-HBED-CC) were purchased from ABX, Radeberg, Germany.

I. Synthesis

I.1 Synthesis of Compounds PS1-PS10

[0224] Unless indicated otherwise, the compounds have been synthesized as follows:

[0225] The synthesis of the pharmacophore Glu-urea-Lys was performed according to Schäfer M et al. (2012), EJNMMI Res. 2(1):23. Briefly, the synthesis started with the formation of the isocyanate of the glutamyl moiety using triphosgene. A resin-immobilized (2-chloro-tritylresin, Merck, Darmstadt) ε-allyloxycarbonyl protected lysine was added and reacted for 16 h with gentle agitation. The resin was filtered off and the allyloxy-protecting group was removed by reacting twice with Pd(PPh.sub.3).sub.4 (0.3 eq.) and morpholine (15 eq.) under ambient conditions (1 h, RT). The resin was split and the linkers were introduced by standard Fmoc solid phase protocols. According to the amino acid sequence of PS1-PS10 the Fmoc-protected amino acids (4 eq. each) with HATU (4 eq.) and DIPEA (10 eq.) were coupled in DMF. After coupling the last amino acid of the sequence, tris(tBu)DOTA (tris(tBu)-ester of 1,4,7,10tetraazacyclododecan-1,4,7,10-tetraacetic acid) (4 eq. each) with HATU (4 eq.) and DIPEA (10 eq.) was coupled in DMF. The product was cleaved from the resin for 3 hours at RT using TFA/TIPS/H2O (95/2.5/2.5, v/v/v).

[0226] All products were purified using RP-HPLC and identified with mass spectrometry.

[0227] Purification was done using a semipreparative column (SemiPrep, Chromolith RP-18e, 100×10 mm; Merck, Darmstadt, Germany). Solvent A consisted of 0.1% aqueous TFA and solvent B was 0.1% TFA in CH.sub.3CN.

[0228] The following compounds were synthesized:

TABLE-US-00002 TABLE A Synthesized Compounds Compound X Structure (PSMA = “Lys-urea-Glu”) PS-1 DOTA-CHx-2NaI-(EH)3-PSMA PS-2 DOTA-(EH)3-CHx-2NaI-PSMA PS-3 DOTA-Chx-(EH)3-2NaI-PSMA PS-4 DOTA-(EH)4-CHx-2NaI-PSMA PS-4.2 DOTA-(HE)3-CHx-2NaI-PSMA PS-5 DOTA-(E)3-CHx-2NaI-PSMA PS-6 DOTA-CHx-2NaI-(E)3-PSMA PS-7 DOTA-(H)3-CHx-2NaI-PSMA PS-8 DOTA-CHx-2NaI-(H)3-PSMA PS-9 DOTA-CHx-(E)3-2NaI-PSMA PS10 DOTA-CHx-(H)3-2NaI-PSMA

I.2 .SUP.68.Ga—Labeling

[0229] The precursor peptides [2 nmol in HEPES buffer (1 M, pH 7), 40 μL] were added to 40 μL [.sup.68Ga]GaCl.sub.4.sup.− (˜30 MBq). The reaction mixture was incubated at 95° C. for 15 minutes. The radiochemical yield (RCY) was determined by HPLC.

I.3 .SUP.177.Lu—Labeling

[0230] The precursor peptides [1 nmol in HEPES buffer (0.1 M, pH 7.2), 50 μL] were added to 10 μL [.sup.177Lu]LuCl.sub.3 (˜30 MBq). The reaction mixture was incubated at 95° C. for 15 minutes. The radiochemical yield (RCY) was determined by HPLC.

I.4 Example 1: Synthesis of DOTA-(EH).SUB.3.—CHx-2NaI-Lys-urea-Glu and DOTA-CHx-2NaI-(EH).SUB.3.-Lys-urea-Glu

[0231] The synthesis of the pharmacophore Glu-urea-Lys was performed according to Schäfer M et al. (2012), EJNMMI Res. 2(1):23. Briefly, the synthesis started with the formation of the isocyanate of the glutamyl moiety using triphosgene. A resin-immobilized (2-chloro-tritylresin, Merck, Darmstadt) F-allyloxycarbonyl protected lysine was added and reacted for 16 h with gentle agitation. The resin was filtered off and the allyloxy-protecting group was removed by reacting twice with Pd(PPh.sub.3).sub.4(0.3 eq.) and morpholine (15 eq.) under ambient conditions (1 h, RT). The resin was split and the linkers were introduced by standard Fmoc solid phase protocols.

[0232] Synthesis of DOTA-(EH).sub.3—CHx-2NaI-Lys-urea-Glu

[0233] In a first step Fmoc-2-NaI—OH and N-Fmoc-tranexamic acid (4 eq. each) with HATU (4 eq.) and DIPEA (10 eq.) were coupled in DMF. For the introduction of (HE).sub.3 the coupling of Fmoc-His(Trt)-OH and Fmoc-Glu(otBu)-OH (4 eq.) was performed using HATU (4 eq.) and DIPEA (10 eq.) in DMF. In order to form (HE).sub.3 the coupling of Fmoc-His(Trt)-OH and Fmoc-Glu(otBu)-OH was repeated, respectively. Subsequently, tris(tBu)DOTA (tris(tBu)-ester of 1,4,7,10tetraazacyclododecan-1,4,7,10-tetraacetic acid) (4 eq. each) with HATU (4 eq.) and DIPEA (10 eq.) was coupled in DMF. The product was cleaved from the resin for 3 hours at RT using TFA/TIPS/H2O (95/2.5/2.5, v/v/v).

[0234] Synthesis of DOTA-CHx-2NaI-(EH).sub.3-Lys-urea-Glu

[0235] In a first step coupling of Fmoc-His(Trt)-OH and Fmoc-Glu(otBu)-OH (4 eq.) was performed using HATU (4 eq.) and DIPEA (10 eq.) in DMF. In order to form (HE).sub.3 the coupling of Fmoc-His(Trt)-OH and Fmoc-Glu(otBu)-OH was repeated, respectively. Afterwards Fmoc-2-NaI—OH and N-Fmoc-tranexamic acid (4 eq. each) with HATU (4 eq.) and DIPEA (10 eq.) were coupled in DMF. Subsequently, tris(tBu)DOTA (tris(tBu)-ester of 1,4,7,10tetraazacyclododecan-1,4,7,10-tetraacetic acid) (4 eq. each) with HATU (4 eq.) and DIPEA (10 eq.) was coupled in DMF. The product was cleaved from the resin for 3 hours at RT using TFA/TIPS/H2O (95/2.5/2.5, v/v/v).

[0236] All products were purified using RP-HPLC and identified with mass spectrometry.

[0237] Purification was done using a NUCLEOSIL column (VP250/21, 5 μm particles, 120-5 C18; Macherey-Nagel, Duren, Germany). Solvent A consisted of 0.1% aqueous TFA and solvent B was 0.1% TFA in CH3CN.

[0238] 177Lu—Labeling

[0239] The precursor peptides [1 nmol in HEPES buffer (0.1 M, pH 7.2), 50 μL] were added to 10 μL [.sup.177Lu]LuCl.sub.3 (˜30 MBq). The reaction mixture was incubated at 95° C. for 30 minutes. The radiochemical yield (RCY) was determined by HPLC.

II. Cell Assays

II.1 Cell Culture

[0240] PSMA.sup.+ LNCaP cells (ATCC CRL-1740) were cultured in RPMI medium. Cells were grown at 37° C. in humidified air with 5% C02 and were harvested using trypsin-ethylenediaminetetraacetic acid.

II.2 Cell Binding and Internalization

[0241] The competitive cell binding assay and internalization experiments were performed according to Eder M et al. (2012), Bioconjug Chem 23(4):688.

[0242] Briefly, the cells (10.sup.5 per well) were incubated with a 0.8 nM solution of .sup.68Ga-labeled radioligand [Glu-urea-Lys(Ahx)].sub.2-HBED-CC (PSMA-10, precursor ordered from ABX, Radeberg, Germany) in the presence of 12 different concentrations of analyte (0-5000 nM, 100 μL/well). After incubation, the mixture was removed and the wells were washed 3 times with PBS using a multiscreen vacuum manifold (Millipore, Billerica, Mass.). Cell-bound radioactivity was measured using a gamma counter (Packard Cobra II, GMI, Minnesota, USA). The 50% inhibitory concentration (IC50) values were calculated by fitting the data using a nonlinear regression algorithm (GraphPad Software).

[0243] For internalization experiments, 10.sup.5 cells per well were seeded in poly-L-lysine coated 24-well cell culture plates 24 h before incubation. After washing, the cells were incubated with 30 nM of the .sup.68Ga- or .sup.177Lu-radiolabeled compound for 45 min at 37° C. and at 4° C., respectively. Cellular uptake was terminated by washing 3 times with 1 mL of ice-cold PBS. To remove surface-bound radioactivity, cells were incubated twice with 0.5 mL glycine-HCl in PBS (50 mM, pH=2.8) for 5 min. The cells were washed with 1 mL of ice-cold PBS and lysed using 0.3 N NaOH (0.5 mL). The surface-bound and the internalized fractions were measured in a gamma counter. The cell uptake was calculated as percent of the initially added radioactivity bound to 10.sup.5 cells [% ID/10.sup.5 cells].

[0244] Statistical Aspects

[0245] All experiments were performed at least in triplicate and repeated at least for three times.

[0246] Quantitative data were expressed as mean±SD. If applicable, means were compared using Student's t test. P values<0.05 were considered statistically significant.

III. μPET Imaging

[0247] For μPET imaging, mice were anaesthetized (2% isoflurane), placed into a small animal PET scanner (PET Focus, Siemens) and injected with 500 pmol .sup.68Ga-labeled peptide per mouse. A 60 min dynamic scan and static scans at 60 and 120 min p.i. were performed. Images were reconstructed and converted to standardized uptake value (SUV) shown in maximum intensity projection (MIP) images and time activity curves. Quantitation was done using a ROI (region of interest) technique and expressed as SUVmean.

IV. Results

[0248] The internalization efficiency of the compounds was determined in order to investigate the influence of the linkers on the binding properties. The results are summarized in Table 1. Both synthesized compounds show significantly higher specific cell surface binding and specific internalization as compared to the reference PSMA-617.

TABLE-US-00003 TABLE 1 Internalization data of the investigated compounds Glu-urea- Lys-2-Nal-Chx-(HE).sub.3-DOTA and Glu-urea-Eys-(HE).sub.3-2-Nal-Chx-DOTA compared to the reference PSMA-617 labeled with.sup.177 Lu. Specific cell Specific surface bound internalized [% ID/10.sup.5 cells] [% ID/10.sup.5 cells] DOTA-CHx-NaI-Lys-urea-Glu 4.36 ± 1.33 2.94 ± 0.35 (PSMA-617)) DOTA-(EH).sub.3-CHx-2NaI-Lys- 9.55 ± 1.61 6.00 ± 0.71 urea-Glu DOTA-CHx-2NaI-(EH).sub.3-Lys- 6.84 ± 0.06 4.32 ± 0.03 urea-Glu

TABLE-US-00004 TABLE 2 Specific Binding Affinity IC.sub.50 (nM) PSMA-617 21.77 ± 3.13 PS-1 55.98 ± 7.70 PS-2  36.96 ± 11.36 PS-3 43.13 ± 9.63 PS-4  46.68 ± 37.30 PS-4.2 27.86 ± 6.93 PS-5 10.40 ± 2.94 PS-6 28.55 ± 8.42 PS-7 22.68 ± 6.47 PS-8  78.64 ± 44.14 PS-9 23.37 ± 9.70 PS10  53.98 ± 20.89

TABLE-US-00005 TABLE 3 Cell surface binding and internalization of the .sup.68Ga-labeled compounds. Cell Surface binding Internalization [% ID/10.sup.5 cells] [% ID/10.sup.5 cells] PSMA-617 0.792 ± 0.134 0.504 ± 0.051 blocked 0.063 ± 0.014 0.117 ± 0.032 PS-1 1.162 ± 0.183 0.676 ± 0.155 blocked 0.069 ± 0.013 0.212 ± 0.037 PS-2 1.333 ± 0.127 0.797 ± 0.122 blocked 0.060 ± 0.017 0.187 ± 0.032 PS-3 1.023 ± 0.140 0.557 ± 0.042 blocked 0.183 ± 0.025 0.317 ± 0.025 PS-4 1.420 ± 0.113 0.676 ± 0.070 blocked 0.083 ± 0.029 0.151 ± 0.048 PS-4.2 1.437 ± 0.138 0.676 ± 0.070 blocked 0.080 ± 0.010 0.113 ± 0.023 PS-5 1.003 ± 0.127 0.725 ± 0.269 blocked 0.055 ± 0.013 0.095 ± 0.026 PS-6 0.767 ± 0.156 0.607 ± 0.136 blocked 0.050 ± 0.020 0.156 ± 0.023 PS-7 0.817 ± 0.047 0.673 ± 0.093 blocked 0.123 ± 0.015 0.207 ± 0.021 PS-8 0.945 ± 0.030 0.600 ± 0.066 blocked 0.038 ± 0.010 0.093 ± 0.033 PS-9 0.650 ± 0.083 0.410 ± 0.090 blocked 0.060 ± 0.021 0.138 ± 0.046 PS10 0.580 ± 0.046 0.523 ± 0.078 blocked 0.027 ± 0.006 0.083 ± 0.006

TABLE-US-00006 TABLE 4 Specific cell surface binding and internalization of the .sup.68Ga-labeled compounds. Specific Cell Surface .sup.68Ga-labeled Binding Specific Internalization compound X [% ID/10.sup.5 cells] [% ID/10.sup.5 cells] PSMA-617 0.72 ± 0.06 0.39 ± 0.06 PS-1 1.09 ± 0.17 0.46 ± 0.11 PS-2 1.27 ± 0.15 0.61 ± 0.15 PS-3 0.84 ± 0.03 0.24 ± 0.02 PS-4 1.33 ± 0.09 0.52 ± 0.04 PS-4.2 1.35 ± 0.28 0.71 ± 0.28 PS-5 0.94 ± 0.13 0.63 ± 0.28 PS-6 0.71 ± 0.12 0.45 ± 0.12 PS-7 0.69 ± 0.11 0.47 ± 0.11 PS-8 0.90 ± 0.03 0.51 ± 0.05 PS-9 0.59 ± 0.09 0.27 ± 0.07 PS10 0.55 ± 0.08 0.44 ± 0.08

[0249] Pharmacokinetic Study in PSMA+ Tumor Bearing Balb/c Nude Mice:

[0250] The time activity curves for kidney after injection of 0.5 nmol .sup.68Ga-labeled compounds in LNCaP-tumor-bearing athymic nude mice (right trunk) up to 60 min p.i. are shown in FIG. 1. (SUV=standardized uptake value)

[0251] Further, the time activity curves for tumor and muscle after injection of 0.5 nmol .sup.68Ga-labeled compound X in LNCaP-tumor-bearing athymic nude mice (right trunk) up to 60 min p.i. (SUV=standardized uptake value) is shown in the following figures:

TABLE-US-00007 TABLE 5 .sup.68Ga-labeled Time activity curve compound X Tumor/Muscle PS-2 FIG. 2.1 PS-3 FIG. 2.2 PS-4 FIG. 2.3 PS-4.2 FIG. 2.4 PS-5 FIG. 2.5 PS-6 FIG. 2.6 PS-7 FIG. 2.7 PS-8 FIG. 2.8 PS-9 FIG. 2.9 PS10 FIG. 2.10

TABLE-US-00008 TABLE 6.1-6-10 Small-animal PET imaging study. Whole-body maximum intensity projection of 0.5 nmol .sup.68Ga-labeled compound X in LNCaP- tumor-bearing athymic nude mice (right trunk) 60 and after 120 min p.i. obtained from small animal PET imaging. .sup.68Ga-labeled compound X 1 h p.i. 2 h p.i. PS-1 FIG. 3.1 A FIG. 3.1 B PS-2 FIG. 3.2 A FIG. 3.2 B PS-3 FIG. 3.3 A FIG. 3.3 B PS-4 FIG. 3.4 A FIG. 3.4 B PS-4.2 FIG. 3.5 A FIG. 3.5 B PS-6 FIG. 3.6 A FIG. 3.6 B PS-7 FIG. 3.7 A FIG. 3.7 B PS-8 FIG. 3.8 A FIG. 3.8 B PS-9 FIG. 3.9 A FIG. 3.9 B PS10 FIG. 3.10 A FIG. 3.10 B