[18F]FPyQCP: A Robust FAP-Targeted PET Tracer Integrating Covalent C−18F Labeling and Radiometal Chelation for Enhanced In Vivo Performance

Abstract Fibroblast activation protein (FAP) is a validated PET imaging target for the tumor microenvironment. Currently, most 18F-labeled FAP PET agents use Al−F chemistry, with Al18F-FAPI-74 leading clinically, whereas C−18F tracers perform less effectively. Here, we developed (4-quinolinoyl)glycyl-2-cyanopyrrolidine (QCP)-based inhibitors incorporating a 6-fluoronicotinamide prosthetic group for stable C−18F labeling. Chelator incorporation improved hydrophilicity and enabled structurally matched radiometal- and 18F-labeled analogs from a common scaffold. The compounds exhibited high FAP inhibitory capacity (Ki = 9.9−56.7 pM) and favorable physicochemical properties (Log P7.4 = −3.1 ± 0.1). The lead tracer, [18F]FPyQCP, was prepared by a one-pot, two-step radiosynthesis in 50−80% yields, with >99% radiochemical purity and molar activity of 74−200 GBq/μmol. In U87 xenografts, [18F]FPyQCP achieved high tumor uptake (23.3 ± 2.1 %ID/g) and favorable tumor-to-blood ratios (12.0 ± 0.3) at 2 h. This modular labeling strategy establishes a versatile platform for next-generation FAP PET tracers and beyond.