Comparative evaluation of the new GRPR‐antagonist 111In‐SB9 and 111In‐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 = [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.