Arene radiofluorination enabled by photoredox-mediated halide interconversion

Abstract Positron emission tomography (PET) is a powerful imaging technology that could visualize and measure metabolic processes in vivo and/or obtain unique information about drug candidates at early stages. Identification of new and improved molecular probes plays a critical role in PET, but its progress is limited in many situations due to the lack of efficient and simple labeling methods to modify biologically active small molecules and/or drugs. Although various approaches have been reported, current methods to radiofluorinate unactivated arenes are still limited. Here we document the discovery of a robust method for constructing C–18F bonds through direct halide/18F conversion in electron-rich halo(hetero)arene substrates. Based on readily available halide precursors and mild photoredox conditions, [18F]F- is efficiently introduced into a broad spectrum of organic molecules, including pharmaceutical compounds in a site-selective manner. Notably, the direct 19F/18F conversion method is demonstrated to be a simple and robust protocol for PET probe screening/preparation: this methodology not only identifies a new cancer imaging agent L-61-18F-COOH after a rapid screening of a tyrosine isomer library; but also allows the simple and high-yielding synthesis of the widely used PET agent L-[18F]FDOPA. Taken together, photoredox-mediated halide/18F interconversion strategies represent an innovative chemical tool to prepare new and clinically significant PET agents that are synthetically inaccessible or cumbersome to achieve by traditional methods.