Zhou_2024_Eur.J.Med.Chem_264_115993

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts in more than 90% of epithelial tumors. Several radiotracers targeting FAPs have been used in clinical settings in recent years. However, the number of (18)F-labeled FAP tracers is still limited. Herein, we aimed to develop (18)F-labeled FAP tracers with optimized pharmacokinetics. Labeling precursors (NOTA-DD-FAPI and NOTA-PD-FAPI) were synthesized and labeled with fluorine-18. The precursors NOTA-DD-FAPI (IC(50) = 0.21 +/- 0.06 nM) and NOTA -PD-FAPI (IC(50) = 0.13 +/- 0.07 nM) showed a higher affinity for FAP compared to NOTA-FAPI-42 (IC(50) = 0.66 +/- 0.19 nM). Novel (18)F-labeled FAP tracers showed a specific uptake, high internalized fraction, and low cellular efflux in vitro. Compared to the clinically used tracer [(18)F]AlF-FAPI-42, both the novel (18)F-labeled FAP tracers, and especially the [(18)F]AlF-PD-FAPI tracer with a higher tumor-to-background ratio demonstrated rapid renal excretion and higher tumor uptake during preclinical evaluation, resulting in images with higher contrast. Thus, [(18)F]AlF-PD-FAPI shows promise for use as a FAP-targeting tracer for clinical translation.