Preclinical Comparison of the⁶⁴Cu- and⁶⁸Ga-Labeled GRPR-Targeted Compounds RM2 and AMTG, as Well as First-in-Humans [⁶⁸Ga]Ga-AMTG PET/CT

Abstract

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 [⁶⁴Cu]Cu-/[⁶⁸Ga]Ga-AMTG ([⁶⁴Cu]Cu-/[⁶⁸Ga]Ga-α-Me-l-Trp⁸-RM2) using [⁶⁴Cu]Cu-/[⁶⁸Ga]Ga-RM2 ([⁶⁴Cu]Cu-/[⁶⁸Ga]Ga-DOTA-Pip⁵-Phe⁶-Gln⁷-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Sta¹³-Leu¹⁴-NH₂) as a reference compound and investigated [⁶⁸Ga]Ga-AMTG in a proof-of-concept study in a PCa patient. <b>Methods:</b> Peptides were labeled with ⁶⁴Cu (80 °C, 1.0 M NaOAc, pH 5.50) and ⁶⁸Ga (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 [⁶⁸Ga]Ga-AMTG were administered intravenously and whole-body PET/CT scans were acquired at 75 min after injection. <b>Results:</b>⁶⁴Cu- and ⁶⁸Ga-labeling proceeded almost quantitatively (&gt;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 ⁶⁴Cu-labeled compounds. Overall biodistribution profiles and tumor-to-background ratios were comparable but slightly enhanced for the ⁶⁸Ga-labeled analogs in most organs. [⁶⁸Ga]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. <b>Conclusion:</b> AMTG is eligible for theranostic use, as labeling with ⁶⁴Cu and ⁶⁸Ga, as well as ¹⁷⁷Lu (known from previous study), does not have a negative influence on its favorable biodistribution pattern. For this reason, further clinical evaluation is warranted.

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