RM2 was shown to be a potent GRPr antagonist. Pharmacokinetics and imaging studies indicate that (111)In-RM2 and (68)Ga-RM2 are ideal candidates for clinical SPECT and PET studies.

Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-positive tumors, especially of subtype 2 (sst2). The clinically used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors determining the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four 64 Cu or 68 Ga radioantagonists for PET of sst2-positive tumors. Methods: The novel antagonist p-Cl-Phecyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH 2 (LM3) was coupled to 3 macrocyclic chelators, namely 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), and DOTA. 64/nat Cu-and 68/nat Ga-NODAGA-LM3 were prepared at room temperature, and 64/nat Cu-CB-TE2A-LM3 and 68/nat Ga-DOTA-LM3 were prepared at 95°C. Binding affinity and antagonistic properties were determined with receptor autoradiography and immunofluorescence microscopy using human embryonic kidney (HEK)-sst2 cells. In vitro internalization and dissociation was evaluated using the same cell line. Biodistribution and small-animal PET studies were performed with HEK-sst2 xenografts. Results: All metallopeptides demonstrated antagonistic properties. The affinities depend on chelator and radiometal and vary about 10-fold; 68/nat Ga-NODAGA-LM3 has the lowest half maximal inhibitory concentration (1.3 6 0.3 nmol/L). The biodistribution studies show impressive tumor uptake at 1 h after injection, particularly of 64 Cu-and 68 Ga-NODAGA-LM3 (;40 percentage injected dose per gram of tissue [%ID/g]), which were proven to be specific. Background clearance was fast and the tumor washout relatively slow for 64 Cu-NODAGA-LM3 (;15 %ID/g, 24 h after injection) and almost negligible for 64 Cu-CB-TE2A-LM3 (26.9 6 3.3 %ID/g and 21.6 6 2.1 %ID/g, 4 and 24 h after injection, respectively). Tumor-to-normal-tissue ratios were significantly higher for 64 Cu-NODAGA-LM3 than for 64 Cu-CB-TE2A-LM3 (tumor-to-kidney, 12.8 6 3.6 and 1.7 6 0.3, respectively; tumor-to-muscle, 1,342 6 115 and 75.2 6 8.5, respectively, at 24 h, P , 0.001). Small-animal PET shows clear tumor localization and high image contrast, especially for 64 Cu-and 68 Ga-NODAGA-LM3. Conclusion: This article demonstrates the strong dependence of the affinity and pharmacokinetics of the somatostatin-based radioantagonists on the chelator and radiometal. 64 Cu-and 68 Ga-NODAGA-LM3 and 64 Cu-CB-TE2A-LM3 are promising candidates for clinical translation because of their favorable pharmacokinetics and the high image contrast on PET scans.

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Tc/EDDA)NH 2 ]-exendin-4 did not result in inferior tumor-to-organ ratios or reduced image quality. All radiopeptides tested showed a high tumor-to-background ratio, resulting in the visualization of small tumors (maximum diameter between 1.0 and 3.2 mm) by SPECT and PET. The only exception was the kidneys, which also showed high uptake. This uptake could be reduced by 49%278% using poly-glutamic acid, Gelofusine, or a combination of the 2. The estimated effective radiation dose was 3.7 mSv/MBq for [Lys 40