Synthesis and Preclinical Evaluation of [<sup>18</sup>F]SiFA-PSMA Inhibitors in a Prostate Cancer Model
Justin J. Bailey, Melinda Wuest, Michael Wagner, Atul Bhardwaj, Carmen Wängler, Björn Wängler, John F. Valliant, Ralf Schirrmacher, Frank Wuest
Abstract
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 (SUV60min 0.73). A substantial increase in molar activity (Am) (from 7.5 ± 0.5 to 86 ± 3 GBq/μmol) led to a significant increase in LNCaP tumor uptake (SUV60min 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.