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 (CF 3 ) groups at C(sp 3 ) sites, despite their growing prevalence in bioactive molecules and radiopharmaceuticals. Here, we present a general approach for late-stage installation of either a [ 18 F]CF 3 or [ 11 C]CF 3 group at a C(sp 3 ) 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 ( 18 F) or carbon-11 ( 11 C). Two long-sought-after radioligands, [ 18 F]SL25.1188 and [ 18 F]PS13, were synthesized, providing longer-lived 18 F analogs of their 11 C counterparts with great promise for human PET imaging.