Evaluation of a novel GRPR antagonist for prostate cancer PET imaging: [64Cu]-DOTHA2-PEG-RM26.

INTRODUCTION:Gastrin releasing peptide receptors (GRPRs) are significantly over-expressed on a large proportion of prostate cancers making them prime candidates for receptor-mediated nuclear imaging by PET. Recently, we synthesized a novel bifunctional chelator (BFC) bearing hydroxamic acid arms (DOTHA2). Here we investigated the potential of a novel DOTHA2-conjugated, 64Cu-radiolabeled GRPR peptide antagonist, [D-Phe6-Sta13-Leu14-NH2]bombesin(6-14) (DOTHA2-PEG-RM26) to visualize prostate tumors by PET imaging. METHODS:DOTHA2-PEG-RM26 was conveniently and efficiently assembled on solid support. The compound was radiolabeled with 64Cu and its affinity, stability, cellular uptake on PC3 prostate cancer cells were evaluated. The in vitro and in vivo behavior of [64Cu]DOTHA2-PEG-RM26 was examined by PET imaging using human PC3 prostate cancer xenografts and its behavior was compared to that of the analogous [64Cu]NOTA-PEG-RM26. RESULTS:The inhibition constant of natCu-DOTHA2-PEG-RM26 was in the low nanomolar range (0.68±0.19 nM). The [64Cu]DOTHA2-PEG-RM26 conjugate was prepared with a labeling yield >95% and molar activity of 56±3 GBq/μmol after a 5-min room temperature labeling. [64Cu]-DOTHA2-PEG-RM26 demonstrated rapid blood and renal clearance as well as a high tumor uptake. Small animal PET images confirmed high and specific uptake in PC3 tumor. Both [64Cu]-DOTHA2-PEG-RM26 and [64Cu]-NOTA-PEG-RM26 displayed similar tumor and normal tissue uptakes at early time point post injection. CONCLUSIONS:[64Cu]-DOTHA2-PEG-RM26 allows visualization of prostate tumors by PET imaging. DOTHA2 enables fast 64Cu chelation under mild condition, and as such could be used advantageously for the development of other 64Cu-labeled peptide-derived PET tracers.