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Title: 99mTc radiotracers based on human GRP(18-27): synthesis and comparative evaluation.
Author: Marsouvanidis PJ, Maina T, Sallegger W, Krenning EP, de Jong M, Nock BA.
Journal: J Nucl Med; 2013 Oct; 54(10):1797-803. PubMed ID: 24009275.
Abstract:
UNLABELLED: Gastrin-releasing peptide receptors (GRPRs) expressed on human tumors can serve as molecular targets for radiolabeled peptide analogs based on the frog tetradecapeptide bombesin (BBN). We have recently expanded this approach toward human GRP(18-27) sequences and introduced (99m)Tc-demomedin C, our first radiotracer based on GRP(18-27), showing favorable biologic characteristics during preclinical evaluation in rodents. We now present a series of (99m)Tc-demomedin C analogs, generated by single-Gly(24) or double-Gly(24)/Met(27) substitutions in the peptide chain, and compare their performance in GRPR-positive in vitro and in vivo models. METHODS: The SARNC ([(N4)Gly(18)]GRP(18-27)) analogs (SARNC2 dAla(24), SARNC3 dAla(24)/Nle(27), SARNC4 dAla(24)/Leu(27), SARNC5 βAla(24), and SARNC6 Sar(24)) were synthesized on the solid support and purified by high-performance liquid chromatography (HPLC). Competition binding experiments against [(125)I-Tyr(4)]BBN were conducted in GRPR-positive PC-3 cell membranes. Internalization of (99m)Tc radioligands was compared in PC-3 cells at 37°C. Metabolic stability was studied by HPLC analysis of blood samples collected 5 min after injection of radiopeptides in mice. Biodistribution was performed by injecting a (99m)Tc-SARNC bolus (185 kBq [5 μCi], 100 μL, 10 pmol of peptide ± 40 nmol of Tyr(4)-BBN: in vivo GRPR blockade) in severe combined immune deficient mice bearing PC-3 xenografts. RESULTS: SARNCs bound to GRPR with high affinity (range of 50% inhibitory concentration [IC50] values, 0.3 nM [SARNC5] to 9.3 nM [SARNC4]). (99m)Tc-SARNCs specifically internalized in PC-3 cells, with (99m)Tc-SARNC5 displaying the fastest internalization rate. (99m)Tc-SARNCs showed distinct degradation rates (17% [(99m)Tc-SARNC3] to >50% [(99m)Tc-SARNC4] remaining intact). All (99m)Tc-SARNCs efficiently and specifically localized in GRPR-positive PC-3 xenografts in mice (4.4 percentage injected dose per gram [%ID/g] [(99m)Tc-SARNC4] to 12.0 %ID/g [(99m)Tc-SARNC2] at 4 h after injection). (99m)Tc-SARNC6 displayed the highest tumor-to-nontumor ratios followed by (99m)Tc-SARNC2. CONCLUSION: This structure-activity relationship study has shown the impact of single-Gly(24) or double-Gly(24)/Met(27) substitutions in the (99m)Tc-SARNC1 motif on key biologic parameters, including GRPR affinity, internalization efficiency, and in vivo stability, which eventually determine the pharmacokinetic profile of resulting radiopeptides. By revealing improved analogs, this study has strengthened the applicability perspectives of radioligands based on human GRP sequences in the detection and therapy of GRPR-expressing tumors in humans.

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