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

Xiaojiang Duan, Zhen Cao, Hua Zhu, Chen Liu, Xiaojun Zhang, Jinming Zhang, Ya’nan Ren, Futao Liu, Xuekang Cai, Xiaoyi Guo, Zhen Xi, Martin G. Pomper, Zhi Yang, Yan Fan, Xing Yang

Research output: Contribution to journalArticlepeer-review


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 68Ga-labeled ODAP-Urea-based ligand, [68Ga]Ga-P137, and first-in-human results. Methods: Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68Ga 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 [68Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [68Ga]Ga-P137 was performed in three patients head-to-head compared to [68Ga]Ga-PSMA-617. Results: Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (Ki of 0.13 to 5.47 nM). [68Ga]Ga-P137 was stable and hydrophilic. [68Ga]Ga-P137 showed higher uptake than [68Ga]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 [68Ga]Ga-P137 was grossly equivalent to that of [68Ga]Ga-PSMA-617 except for within the urinary tract, in which [68Ga]Ga-P137 demonstrated lower uptake. Conclusion: The optimized ODAP-Urea-based ligand [68Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [68Ga]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.

Original languageEnglish (US)
Pages (from-to)1030-1040
Number of pages11
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Issue number3
StatePublished - Feb 2022


  • Oxalyldiaminopropionic acid-urea (ODAP-Urea) ligand
  • Prostate cancer
  • Prostate-specific membrane antigen (PSMA)
  • Translational imaging

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging


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