Molecular Imaging of Gastrin-Releasing Peptide Receptor-Positive Tumors in Mice Using64Cu- and86Y-DOTA−(Pro1,Tyr4)-Bombesin(1−14)

Abstract

Bombesin is a tetradecapeptide neurohormone that binds to gastrin-releasing peptide receptors (GRPR). GRPRs have been found in a variety of cancers including invasive breast and prostate tumors. The peptide MP2346 (DOTA−(Pro¹,Tyr⁴)-bombesin(1−14)) was designed to bind to these GRP receptors. This study was undertaken to evaluate radiolabeled MP2346 as a positron emission tomography (PET) imaging agent. MP2346 was radiolabeled, in high radiochemical purity, with the positron-emitting nuclides ⁶⁴Cu (t_1/2 = 12.7 h, β⁺ = 19.3%, E_avg = 278 keV) and ⁸⁶Y (t_1/2 = 14.7 h, β⁺ = 33%, E_avg = 664 keV). ⁶⁴Cu-MP2346 and ⁸⁶Y-MP2346 were studied in vitro for cellular internalization by GRPR-expressing PC-3 (human prostate adenocarcinoma) cells. Both ⁶⁴Cu- and ⁸⁶Y-MP2346 were studied in vivo for tissue distribution in nude mice with PC-3 tumors. Biodistribution in PC3 tumor-bearing mice demonstrated higher tumor uptake, but lower liver retention, in animals injected with ⁸⁶Y-MP2346 compared to ⁶⁴Cu-MP2346. Receptor-mediated uptake was confirmed by a significant reduction in uptake in the PC-3 tumor and other receptor-rich tissues by coinjection of a blockade. Small animal PET/CT imaging was carried out in mice bearing PC-3 tumors and rats bearing AR42J tumors. It was possible to delineate PC-3 tumors in vivo with ⁶⁴Cu-MP2346, but superior ⁸⁶Y-MP2346-PET images were obtained due to lower uptake in clearance organs and lower background activity. The ⁸⁶Y analogue demonstrated excellent PET image quality in models of prostate cancer for the delineation of the GRPR-rich tumors and warrants further investigation.