68Ga-labeled ODAP-Urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent

Purpose Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here, we report the synthesis of an optimized 68 Ga-labeled ODAP-Urea-based ligand, [ 68 Ga]Ga-P 137 , and first-in-human results. Methods Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68 Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice-bearing 22Rv1 prostate tumors by microPET. Lead compound [ 68 Ga]Ga-P 137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [ 68 Ga]Ga-P 137 was performed in three patients head-to-head compared to [ 68 Ga]Ga-PSMA-617. Results Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA ( K i of 0.13 to 5.47 nM). [ 68 Ga]Ga-P 137 was stable and hydrophilic. [ 68 Ga]Ga-P 137 showed higher uptake than [ 68 Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98%IA/g vs 3.41 ± 1.31%IA/g at 60-min post-injection. In human studies, the normal organ biodistribution of [ 68 Ga]Ga-P 137 was grossly equivalent to that of [ 68 Ga]Ga-PSMA-617 except for within the urinary tract, in which [ 68 Ga]Ga-P 137 demonstrated lower uptake. Conclusion The optimized ODAP-Urea-based ligand [ 68 Ga]Ga-P 137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [ 68 Ga]Ga-PSMA-617, in a preliminary, first-in-human study. Trial registration ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725