Development and clinical potential of ¹⁸F-PSiMA for prostate cancer PET imaging

Prostate-specific membrane antigen (PSMA) is a key target for diagnosing prostate cancer through positron emission tomography (PET). While ⁶⁸Ga-labeled PSMA compounds are widely used, ¹⁸F-labeled PSMA inhibitors have gained traction for clinical tumor imaging. We previously investigated PSMA-targeting compounds based on the Lys-urea-Glu motif, incorporating a silicon fluoride-acceptor (SiFA) and chemical auxiliaries to enhance <i>in vivo</i> biodistribution. This led to the development of ¹⁸F-PSiMA, a SiFA-based radiotracer with an optimized linker exhibiting favorable PSMA potency (IC₅₀ = 154 ± 47 nM in LNCaP cells). ¹⁸F-PSiMA radiosynthesis with low to high concentrations of ¹⁸F and precursor achieved molar activities (<i>A</i> _m) of 10.9-82.5 GBq μmol^-1 and showed a 24-38% increase in tumor uptake in LNCaP tumors (SUV_60min 1.56 ± 0.18; 7.23 ± 0.75% ID per g at lower <i>A</i> _m and SUV_60min 1.90 ± 0.29; 9.62 ± 1.29% ID per g at higher <i>A</i> _m) compared to our previous lead, ¹⁸F-SiFA-Asp₂-PEG₃-PSMA. PSMA specificity was confirmed by a 20 ± 10% reduction in SUV_60min upon co-injection with DCFPyl. These promising <i>in vitro</i> and <i>in vivo</i> results support further clinical translation of ¹⁸F-PSiMA for prostate cancer PET imaging.