Exploring 18F/19F Isotopic Exchange for the Synthesis of [18F]Trifluoromethylated Arenes

Abstract

The presence of the trifluoromethyl aromatic (Ar–CF₃) moiety can enhance the interactions with targets, membrane permeability, metabolic stability, and drug efficacy. It also prioritizes positron emission tomography (PET) imaging without altering original drug structures. Although the simplicity of ¹⁸F/¹⁹F isotope exchange has flourished in boron-, silicon-, phosphorus- and sulfur-based ¹⁸F-radiochemistry, its application to CF₂(sp³)–¹⁸F bond formation remains challenging. Herein, we reported the radiolabeling of Ar–CF₃ derivatives via ¹⁸F/¹⁹F isotopic exchange across a range of substrates (13 examples), achieving favorable nondecay corrected radiochemical yields (up to 27.2 ± 1.3%) and molar activities (2.8 ± 0.2 GBq·μmol^–1). The utility of this isotopic exchange-based strategy for trifluoromethylated arene molecules was further demonstrated through the radiolabeling of other Ar–CF₃-containing molecules including ponatinib, and through PET imaging using ¹⁸F-labeled selinexor. Overall, this in situ ¹⁸F-radiolabeling strategy for Ar–CF₃-containing small molecules expands the scope for developing new PET tracers, demonstrates potential application in drug discovery, and offers an efficient approach for synthesizing small-molecule tracers for PET imaging.