Trifluoromethylation of alkyl electrophiles with ¹¹ C- or ¹⁸ F-labeled fluoroform for PET applications

Continued development of positron emission tomography (PET) tracers is essential for advancing molecular imaging in biomedical research and clinical diagnostics. A long-standing limitation in radiochemistry for PET imaging has been the lack of general methods for radiolabeling trifluoromethyl (CF₃) groups at C(sp³) sites, despite their growing prevalence in bioactive molecules and radiopharmaceuticals. Here, we present a general approach for late-stage installation of either a [¹⁸F]CF₃ or [¹¹C]CF₃ group at a C(sp³) site. This method leverages unusual copper-mediated radiotrifluoromethylation of alkyl halides and alkyl carboxylic acids by halogen atom transfer and photoredox catalysis, respectively. More than 50 complex molecules and pharmaceutical agents were efficiently labeled with fluorine-18 (¹⁸F) or carbon-11 (¹¹C). Two long-sought-after radioligands, [¹⁸F]SL25.1188 and [¹⁸F]PS13, were synthesized, providing longer-lived ¹⁸F analogs of their ¹¹C counterparts with great promise for human PET imaging.