Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate cancer, representing attractive targets for diagnosis and therapy with bombesin (BBN)-like radioligands. GRPR-antagonists have lately attracted much attention owing to inherent biosafety and favorable pharmacokinetics. We herein present the GRPR-antagonist SB9 structurally resembling the known BBN-based agonist AMBA (SB9 = [Leu13NHEt-desMet14]AMBA). The profiles of 111In-SB9 and 111In-AMBA were directly compared in PC-3 cells and tumor-bearing mice. SB9 and AMBA displayed high GRPR affinities. 111In-AMBA strongly internalized in PC-3 cells, while 111In-SB9 remained bound on the cell surface showing a typical GRPR-radioantagonist profile. 111In-SB9 was more stable than 111In-AMBA, but coinjection of the neprilysin (NEP) inhibitor phosphoramidon (PA) stabilized both in vivo. The radioligands displayed high tumor uptake (20.23 ± 3.41 %ID/g and 18.53 ± 1.54 %ID/g, respectively, at 4 hours pi), but 111In-SB9 washed faster from background. PA coinjection led to significant increase of tumor uptake, combined with better clearance for 111In-SB9. In short, this study has revealed superior pharmacokinetics and higher stability for the GRPR-antagonist 111In-SB9 vs the corresponding agonist 111In-AMBA consolidating previous evidence that GRPR antagonists are preferable to agonists for tumor imaging and therapy. It has also demonstrated that further pharmacokinetic improvements were feasible by in situ metabolic radioligand stabilization using PA.

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Keywords 111In-AMBA, 111In-labeled GRPR-antagonist, bombesin, GRPR targeting, in vivo neprilysin inhibition, neprilysin, phosphoramidon, prostate cancer
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Journal Journal of Labelled Compounds and Radiopharmaceuticals
Lymperis, E, Kaloudi, A, Kanellopoulos, P. (Panagiotis), Krenning, E.P, de Jong, M, Maina, T, & Nock, B.A. (2019). Comparative evaluation of the new GRPR-antagonist 111In-SB9 and 111In-AMBA in prostate cancer models: Implications of in vivo stability. Journal of Labelled Compounds and Radiopharmaceuticals. doi:10.1002/jlcr.3733