Exploring Covalent C– 18 F Bonding Strategies in the Design of FAP-Targeted Radiotracers

Quinoline-based fibroblast activation protein inhibitors (FAPIs) have shown great potential for tumor diagnosis and therapy. To address the instability and limited applicability of 18FAlF coordination chemistry, we designed nine fluorinated FAPIs incorporating the UAMC-1110 pharmacophore, enabling 18F-labeling through the formation of stable C-18F covalent bonds. All compounds exhibited high fibroblast activation protein affinities (Ki = 0.092-1.22 nM). Among them, 18F54, synthesized via copper-catalyzed click chemistry, demonstrated excellent in vivo performance, achieving a high tumor-to-muscle ratio (TMR = 11 ± 3.1) at 60 min postinjection (p.i.) and sustained tumor retention, with only a 19% decrease from 30 to 120 min p.i. These findings support 18F54 as a promising candidate for FAP-targeted imaging and highlight C-18F bond formation as a compelling alternative to 18FAlF methods for developing next-generation FAP-targeted positron emission tomography tracers.