Comparative evaluation of the new GRPR-antagonist In-SB9 and In-AMBA in prostate cancer models - Implications of in vivo stability.

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 = [Leu(13)NHEt-desMet(14)]AMBA). The profiles of In-111-SB9 and In-111-AMBA were directly compared in PC-3 cells and tumor-bearing mice. SB9 and AMBA displayed high GRPR affinities. In-111-AMBA strongly internalized in PC-3 cells, while In-111-SB9 remained bound on the cell surface showing a typical GRPR-radioantagonist profile. In-111-SB9 was more stable than In-111-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 In-111-SB9 washed faster from background. PA coinjection led to significant increase of tumor uptake, combined with better clearance for In-111-SB9. In short, this study has revealed superior pharmacokinetics and higher stability for the GRPR-antagonist In-111-SB9 vs the corresponding agonist In-111-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.