Preclinical Comparison of the 64 Cu- and 68 Ga-Labeled GRPR-Targeted Compounds RM2 and AMTG, as Well as First-in-Humans [ 68 Ga]Ga-AMTG PET/CT.

Despite the recent success of prostate-specific membrane antigen (PSMA)-targeted compounds for theranostic use in prostate cancer (PCa), alternative options for the detection and treatment of PSMA-negative lesions are needed. We have recently developed a novel gastrin-releasing peptide receptor (GRPR) ligand with improved metabolic stability, which might improve diagnostic and therapeutic efficacy and could be valuable for PSMA-negative PCa patients. Our aim was to examine its suitability for theranostic use. We performed a comparative preclinical study on [64 Cu]Cu-/[68 Ga]Ga-AMTG ([64 Cu]Cu-/[68 Ga]Ga-α-Me-l-Trp8 -RM2) using [64 Cu]Cu-/[68 Ga]Ga-RM2 ([64 Cu]Cu-/[68 Ga]Ga-DOTA-Pip5 -Phe6 -Gln7 -Trp8 -Ala9 -Val10 -Gly11 -His12 -Sta13 -Leu14 -NH2 ) as a reference compound and investigated [68 Ga]Ga-AMTG in a proof-of-concept study in a PCa patient. Methods: Peptides were labeled with 64 Cu (80 °C, 1.0 M NaOAc, pH 5.50) and 68 Ga (90 °C, 0.25 M NaOAc, pH 4.50). GRPR affinity (half-maximal inhibitory concentration, room temperature, 2 h) and GRPR-mediated internalization (37 °C, 60 min) were examined on PC-3 cells. Biodistribution studies were performed at 1 h after injection in PC-3 tumor-bearing mice. For a first-in-humans application, 173 MBq of [68 Ga]Ga-AMTG were administered intravenously and whole-body PET/CT scans were acquired at 75 min after injection. Results: 64 Cu- and 68 Ga-labeling proceeded almost quantitatively (>98%). All compounds revealed similarly high GRPR affinity (half-maximal inhibitory concentration, 1.5-4.0 nM) and high receptor-bound fractions (79%-84% of cell-associated activity). In vivo, high activity levels (percentage injected dose per gram) were found in the PC-3 tumor (14.1-15.1 %ID/g) and the pancreas (12.6-30.7 %ID/g), whereas further off-target accumulation was low at 1 h after injection, except for elevated liver uptake observed for both 64 Cu-labeled compounds. Overall biodistribution profiles and tumor-to-background ratios were comparable but slightly enhanced for the 68 Ga-labeled analogs in most organs. [68 Ga]Ga-AMTG confirmed the favorable pharmacokinetics-as evident from preclinical studies-in a patient with metastasized castration-resistant PCa showing intense uptake in several lesions. Conclusion: AMTG is eligible for theranostic use, as labeling with 64 Cu and 68 Ga, as well as 177 Lu (known from previous study), does not have a negative influence on its favorable biodistribution pattern. For this reason, further clinical evaluation is warranted.