Radiometal-Dependent Biological Profile of the Radiolabeled Gastrin-Releasing Peptide Receptor Antagonist SB3 in Cancer Theranostics: Metabolic and Biodistribution Patterns Defined by Neprilysin

Abstract

Recent advances in oncology involve the use of diagnostic/therapeutic radionuclide-carrier pairs that target cancer cells, offering exciting opportunities for personalized patient treatment. Theranostic gastrin-releasing peptide receptor (GRPR)-directed radiopeptides have been proposed for the management of GRPR-expressing prostate and breast cancers. We have recently introduced the PET tracer ⁶⁸Ga-SB3 (SB3, DOTA- p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), a receptor-radioantagonist that enables the visualization of GRPR-positive lesions in humans. Aiming to fully assess the theranostic potential of SB3, we herein report on the impact of switching ⁶⁸Ga to ¹¹¹In/¹⁷⁷Lu-label on the biological properties of resulting radiopeptides. Notably, the bioavailability of ¹¹¹In/¹⁷⁷Lu-SB3 in mice drastically deteriorated compared with metabolically robust ⁶⁸Ga-SB3, and as a result led to poorer ¹¹¹In/¹⁷⁷Lu-SB3 uptake in GRPR-positive PC-3 xenografts. The peptide cleavage sites were identified by chromatographic comparison of blood samples from mice intravenously receiving ¹¹¹In/¹⁷⁷Lu-SB3 with each of newly synthesized ¹¹¹In/¹⁷⁷Lu-SB3-fragments. Coinjection of the radioconjugates with the neprilysin (NEP)-inhibitor phosphoramidon led to full stabilization of ¹¹¹In/¹⁷⁷Lu-SB3 in peripheral mouse blood and resulted in markedly enhanced radiolabel uptake in the PC-3 tumors. In conclusion, in situ NEP-inhibition led to indistinguishable ⁶⁸Ga/¹¹¹In/¹⁷⁷Lu-SB3 profiles in mice emphasizing the theranostic prospects of SB3 for clinical use.