Synthesis and Preclinical Evaluation of [18F]SiFA-PSMA Inhibitors in a Prostate Cancer Model

Positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) with gallium-68 (⁶⁸Ga) and fluorine-18 (¹⁸F) radiotracers has aroused tremendous interest over the past few years. The use of organosilicon-[¹⁸F]fluoride acceptors (SiFA) conjugated to urea-based peptidomimetic PSMA inhibitors provides a "kit-like" multidose synthesis technology. Nine novel ¹⁸F-labeled SiFA-bearing PSMA inhibitors with different linker moieties were synthesized and analyzed for their in vitro binding against [¹²⁵I]I-TAAG-PSMA in LNCaP cells. IC₅₀ values ranged from 58-570 nM. Among all compounds, [¹⁸F]SiFA-Asp₂-PEG₃-PSMA (IC₅₀ = 125 nM) showed the highest tumor uptake in LNCaP tumors (SUV_60min 0.73). A substantial increase in molar activity (A_m) (from 7.5 ± 0.5 to 86 ± 3 GBq/μmol) led to a significant increase in LNCaP tumor uptake (SUV_60min 1.18; Δ 0.45 corresponding to +62%). In vivo blocking with DCFPyL resulted in -32% uptake after 60 min. The SiFA-isotopic exchange chemistry offers a method that is readily adaptable for a "kit-type" labeling procedure and clinical translation.