[18F]FPyQCP: A Robust FAP-Targeted PET Tracer Integrating Covalent C−18F Labeling and Radiometal Chelation for Enhanced In Vivo Performance
Sangeeta Ray Banerjee, Srikanth Boinapally, Il Minn, Deepankar Das, Laurence Carroll, Anand K. Thotakura, Hyojin Cha, Alla Lisok, Rajan Singh, Suresh Alati, Hwanhee Nam, Yong Du, Andrew G. Horti, Martin G. PomperAbstract
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.