Exploring Covalent C-18F 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 [¹⁸F]AlF 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 (K_i = 0.092-1.22 nM). Among them, [¹⁸F]54, 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 [¹⁸F]54 as a promising candidate for FAP-targeted imaging and highlight C-¹⁸F bond formation as a compelling alternative to [¹⁸F]AlF methods for developing next-generation FAP-targeted positron emission tomography tracers.