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

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 (SUV_max = 11.40 ± 1.75) demonstrated significantly superior tumor uptake over the clinically used [¹⁸F]DCFPyL (SUV_max = 1.49 ± 0.31) and [⁶⁸Ga]PSMA-11 (SUV_max = 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.