Abstract

The high kidney uptake of prostate-specific membrane antigen (PSMA) radiotracers remains a significant challenge in the clinical diagnosis and treatment of prostate cancer (PCa). The aim of this study was to reduce the absolute kidney uptake of PSMA tracers by modifying targeting groups, thereby increasing the tumour-to-kidney (T/K) ratio. [^99mTc]Tc-AuK-NapLPRO-HYNIC-EDDA demonstrated the most prominent imaging potential. It bound stably within the active cavity of the PSMA protein with nanomolar affinity (Kd = 14.73 nM). Density functional theory (DFT) and molecular dynamics provide a theoretical framework for understanding tracer coordination structures and ligand-protein interactions. [^99mTc]Tc-AuK-NapLPRO-HYNIC-EDDA effectively reduced kidney uptake (1.19 ± 0.19% ID/g, 4 h) and resulted in good tumour retention, with rapid clearance from nontarget organs resulting in a high target-to-background ratios (TBRs). High-contrast SPECT/CT images were obtained within 2 h to 4 h postinjection, indicating that [^99mTc]Tc-AuK-NapLPRO-HYNIC-EDDA holds great potential for both standard and time-lapse imaging in PCa.

Full Paper DOI

Recommended citation: J Med Chem. 2026,69(5),5887–5900.
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