The advent of total-body Positron Emission Tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in 18F-radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2.  However, access to 18F-difluoromethylated molecules in high molar activity (Am) is largely an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. We report herein a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of Am is solved using an assay examining the likelihood of isotopic dilution upon variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]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. Impact is illustrated with the labelling of highly complex and functionalised biologically relevant molecules and radiotracers.



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