| Summary: | <p>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<sup>1</sup>. Such possibilities have accelerated progress in <sup>18</sup>F-radiochemistry with numerous methods available to <sup>18</sup>F-label (hetero)arenes and alkanes<sup>2</sup>. However, access to <sup>18</sup>F-difluoromethylated molecules in high molar activity (A<sub>m</sub>) is largely an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery<sup>3</sup>. We report herein a general solution by introducing carbene chemistry to the field of nuclear imaging with a [<sup>18</sup>F]difluorocarbene reagent capable of a myriad of <sup>18</sup>F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this <sup>18</sup>F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of A<sub>m</sub> 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 [<sup>18</sup>F]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, <em>N</em>-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.</p>
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