[F-18]Difluorocarbene for positron emission tomography

The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology(1). Such possibilities have accelerated progress in fluorine-18 (F-18) radiochemistry with numerous methods available to F-18-label (hetero)arenes and alkanes(2). However, access to F-18-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery(3). Here we report a general solution by introducing carbene chemistry to the field of nuclear imaging with a [F-18]difluorocarbene reagent capable of a myriad of F-18-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this F-18-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of molar activity is solved using an assay examining the likelihood of isotopic dilution on variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [F-18]difluorocarbene-based reactions including O-H, S-H and N-H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes and aryl boronic acids that are easy to install. The impact is illustrated with the labelling of highly complex and functionalized biologically relevant molecules and radiotracers.