Discovery of Novel KuE PSMA PET Tracers through Structure Fine-Tuning and Direct Photocatalyzed 18F-Deoxyfluorination

  • J Med Chem. 2025 Jul 24;68(14):14594-14608. doi: 10.1021/acs.jmedchem.5c00741.
Yueqi Wang  1 ,  Mingxing Hu  1 ,  Junjie Wu  2 ,  Lili Pan  1 ,  Huijun Zhou  1 ,  Li Li  1 ,  Weihong Kuang  3 ,  Yongmei Xie  2 ,  Wei Chen  1
Affiliations
  • 1. Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
  • 3. Department of Psychiatry and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 40627974 DOI: 10.1021/acs.jmedchem.5c00741
Abstract

Prostate-specific membrane antigen (PSMA) PET imaging has been recognized as an effective modality for early and accurate prostate Cancer (PCa) diagnosis. While the 18F-labeled PSMA tracer was initially approved for clinical use, the structure-activity relationship (SAR) has been underexplored due to limited accessibility of the tracers. Herein, we designed and synthesized a group of PSMA PET tracers through structure-based meticulous optimization for potential interactions at the amphipathic S1 site. Notably, the 18F-fluorinated electron-neutral and -rich aryl moiety instead was incorporated into the KuE motif through direct photocatalyzed 18F-deoxyfluorination. The preferred [18F]1c (SUVmax = 11.40 ± 1.75) demonstrated significantly superior tumor uptake over the clinically used [18F]DCFPyL (SUVmax = 1.49 ± 0.31) and [68Ga]PSMA-11 (SUVmax = 4.2 ± 0.35) in LNCaP mice model and exhibited favorable metabolic properties. Moreover, the [18F]1c was successfully produced on a commercial autosynthesis module and further evaluated on a rhesus macaque, which holds great potential for clinical transformation of PCa diagnosis.

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