Radiosynthesis and biological evaluation of F-18-labeled bispecific heterodimer targeted dual gastrin-releasing peptide receptor and prostate-specific membrane antigen for prostate cancer imaging

Objective Approximately 5% of prostatic primary tumors and 15% of metastatic tumors were found to be prostate-specific membrane antigen (PSMA)-negative. Targeting gastrin-releasing peptide receptor (GRPR) has been shown to complement patients with PSMA-negative prostate cancer (PCa). Based on previous findings, simultaneously targeting PSMA and GRPR imaging may improve the diagnosis of PCa. In this study, we report the radiosynthesis and biological evaluation of a bispecific heterodimer of NOTA-GRPR-PSMA that targeted both PSMA and GRPR for extended PCa imaging. Methods NOTA-GRPR-PSMA was labeled using the (AlF)-F-18-chelating one-step method. The competitive combination experiment and specific binding assay were performed in vitro using 22Rv1 (PSMA+) and PC-3 (GRPR+) cells. To determine the distribution and specificity in vivo, biodistribution and micro-PET/computed tomography of [F-18]AlF-GRPR-PSMA were performed on mice bearing 22Rv1 or PC-3 tumors. Results [F-18]AlF-GRPR-PSMA had a radiochemical purity of over 98% and demonstrated high stability in vivo and in vitro, with a LogD of -1.2 +/- 0.05. Cell uptake and inhibition studies of [F-18]AlF-GRPR-PSMA in 22Rv1 and PC-3 cells revealed bispecific GRPR and PSMA bindings. According to the biodistribution study and PET imaging, [F-18]AlF-GRPR-PSMA was mainly excreted through the kidney. Tumor uptake was high in 22Rv1 tumor (10.1 +/- 0.4 %ID/g) and moderate in PC-3 tumor (2.1 +/- 0.6 %ID/g) 2 h p.i., whereas blocking studies significantly decreased the tumor uptake of 22Rv1 and PC-3. Conclusion [F-18]AlF-GRPR-PSMA has the potential to simultaneously target PSMA and GRPR for PCa imaging.