Preclinical Comparison of the Cu- and Ga-Labeled GRPR-Targeted Compounds RM2 and AMTG, as Well as First-in-Humans [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 [Cu]Cu-/[Ga]Ga-AMTG ([Cu]Cu-/[Ga]Ga-α-Me-l-Trp-RM2) using [Cu]Cu-/[Ga]Ga-RM2 ([Cu]Cu-/[Ga]Ga-DOTA-Pip-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH) as a reference compound and investigated [Ga]Ga-AMTG in a proof-of-concept study in a PCa patient. Peptides were labeled with Cu (80 °C, 1.0 M NaOAc, pH 5.50) and 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 [Ga]Ga-AMTG were administered intravenously and whole-body PET/CT scans were acquired at 75 min after injection. Cu- and 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 Cu-labeled compounds. Overall biodistribution profiles and tumor-to-background ratios were comparable but slightly enhanced for the Ga-labeled analogs in most organs. [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. AMTG is eligible for theranostic use, as labeling with Cu and Ga, as well as Lu (known from previous study), does not have a negative influence on its favorable biodistribution pattern. For this reason, further clinical evaluation is warranted.