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 NM 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 %ID/g vs 3.41 ± 1.31 %ID/g at 60 min post-injection. In humans 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.