A Comparative Study of Radiolabeled Bombesin Analogs for the PET Imaging of Prostate Cancer

Abstract

Radiolabeled bombesin (BBN) analogs that bind to the gastrin-releasing peptide receptor (GRPR) represent a topic of active investigation for the development of molecular probes for PET or SPECT of prostate cancer (PCa). RM1 and AMBA have been identified as the 2 most promising BBN peptides for GRPR-targeted cancer imaging and therapy. In this study, to develop a clinically translatable BBN-based PET probe, we synthesized and evaluated 18F-AlF- (aluminum-fluoride) and 64Cu-radiolabeled RM1 and AMBA analogs for their potential application in PET imaging of PCa. Methods 1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA)–conjugated RM1 and AMBA were synthesized and tested for their GRPR-binding affinities. The NODAGA-RM1 and NODAGA-AMBA probes were further radiolabeled with 64Cu or 18F-AlF and then evaluated in a subcutaneous PCa xenograft model (PC3) by small-animal PET imaging and bio-distribution studies. Results NODAGA-RM1 and NODAGA-AMBA can be successfully synthesized and radiolabeled with 64Cu and 18F-AlF. 64Cu- and 18F-AlF-labeled NODAGA-RM1 demonstrated excellent serum stability and tumor-imaging properties in the in vitro stability assays and in vivo imaging studies. 64Cu-NODAGA-RM1 exhibited tumor uptake values of 3.3 ± 0.38, 3.0 ± 0.76, and 3.5 ± 1.0 percentage injected dose per gram of tissue (%ID/g) at 0.5, 1.5, and 4 h after injection, respectively. 18F-AlF-NODAGA-RM1 exhibited tumor uptake values of 4.6 ± 1.5, 4.0 ± 0.87, and 3.9 ± 0.48 %ID/g at 0.5, 1, and 2 h, respectively. Conclusion The high-stability, efficient tumor uptake and optimal pharmacokinetic properties highlight 18F-AlF-NODAGA-RM1 as a probe with great potential and clinical application for the PET imaging of prostate cancer.

Preclinical Comparison of Al18F- and 68Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

“…The uptake of Al 18 F-JMV5132 in bone was relatively low (0.52 6 0.13 %ID/g 2 h after injection), in comparison with the values reported for the Al 18 F-labeled RM1 derivative (1.58 %ID/g 2 h after injection) (31). The increased uptake of Al 18 F-JMV5132 and 68 Ga-JMV5132 in the gallbladder, liver, and gastrointestinal excretions indicates partial hepatobiliary excretion of the tracers, because of their higher lipophilicity, which may be caused by the benzyl group.…”

“…This novel technique has been successfully applied to several peptides, including a GRPR agonist (28) and recently to GRPR antagonists (31,32). Recently, McBride et al reported the labeling of peptides with Al 18 F in a 1-pot, 1-step procedure using the NODA-MPAA chelator (26,33), leading to a kit formulation, after which the labeled peptide could be purified by solid-phase extraction.…”

N-Terminal Modifications Improve the Receptor Affinity and Pharmacokinetics of Radiolabeled Peptidic Gastrin-Releasing Peptide Receptor Antagonists: Examples of 68Ga- and 64Cu-Labeled Peptides for PET Imaging

“…Different retention times of the tracers in the tumor and pancreas have also been observed for other GRPr antagonists already studied (8)(9)(10)29,30), but this was not the case for GRPr agonists (16) for which pancreas uptake was found to be high over time. Recently, Liu et al (31) have coupled NODAGA to RM1 (antagonist) and to AMBA (agonist) and labeled the 2 conjugates with 64 Cu and 18 F-AlF. They found low but specific tumor uptake for both the antagonist and the agonist, but the former showed significantly lower abdominal uptake.…”

“…Innovative developments using agonists hybridized with other targeting units such as a v b 3 integrins or hypoxia-targeting agents such as 2-nitroimidazoles (25). The successful pharmacokinetic performance of somatostatin-based antagonistic radiotracers preclinically (6,26,27) and clinically (28) led several research groups to develop GRPr antagonists, which indeed exhibit pharmacokinetics superior to agonists (7)(8)(9)(10)(29)(30)(31)(32). Despite these promising data with the first antagonists, there is no consensus that antagonists are superior to agonists targeting the GRPr (33,34).…”

Bombesin-Targeted PET of Prostate Cancer

“…Liu et al (27) studied the same 2 peptides (RM1 and AMBA). Instead of DOTA, they used NODAGA for labeling with 64 Cu and 18 F. They concluded that the antagonist exhibited higher tumor uptake and more favorable pharmacokinetics (27), consistent with the results of Mansi et al (14).…”