Comparative evaluation of the new GRPR‐antagonist 111In‐SB9 and 111In‐AMBA in prostate cancer models: Implications of in vivo stability. (13th June 2019)

• Record Type: Journal Article
• Authors: Lymperis, Emmanouil; Kaloudi, Aikaterini; Kanellopoulos, Panagiotis; Krenning, Eric P.; de Jong, Marion; Maina, Theodosia; Nock, Berthold A.
• Other Names: Maina‐Nock Theodosia guestEditor.; Nock Berthold guestEditor.
• Is Part Of: Journal of labelled compounds & radiopharmaceuticals. Volume 62:Number 10(2019)
• Page Start: 646
• Page End: 655
• Publication Date: 2019-06-13
• Subjects: 111In‐AMBA -- 111In‐labeled GRPR‐antagonist -- bombesin -- GRPR targeting -- in vivo neprilysin inhibition -- neprilysin -- phosphoramidon -- prostate cancer; Tracers (Chemistry) -- Periodicals; Radiopharmaceuticals -- Periodicals; 615.8424
• DOI: 10.1002/jlcr.3733
• Languages: English
• ISSNs: 0362-4803

Abstract

Abstract : 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‐ des Met 14 ]AMBA). The profiles of 111 In‐SB9 and 111 In‐AMBA were directly compared in PC‐3 cells and tumor‐bearing mice. SB9 and AMBA displayed high GRPR affinities. 111 In‐AMBA strongly internalized in PC‐3 cells, while 111 In‐SB9 remained bound on the cell surface showing a typical GRPR‐radioantagonist profile. 111 In‐SB9 was more stable than 111 In‐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 111 In‐SB9 washed faster from background. PA coinjection led to significant increase of tumor uptake, combined with better clearance for 111 In‐SB9. In short, this study has revealed superior pharmacokinetics and higher stability for the GRPR‐antagonist 111 In‐SB9 vs the corresponding agonist 111 In‐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. Abstract : Direct comparison of the GRPR‐antagonist 111 In‐SB9 vs the structurally related agonist 111 In‐AMBA revealed superior pharmacokinetics and stability for 111 In‐SB9, supporting the recent shift of paradigm toward GRPR‐radioantagonists in tumor theranostics. Notably, in situ metabolic stabilization with the neprilysin‐inhibitor phosphoramidon further improved pharmacokinetics of 111 In‐SB9 in mice.