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

Abstract

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.