Fluorine-18 labelled arenes and heteroarenes are an important class of substrates in medical imaging by PET. Traditionally, these molecules are prepared via nucleophilic aromatic substitution (SNAr) reactions of an appropriately activated substrate, which limits the scope of molecules that can be radiolabelled with [18F]fluoride. Despite extensive efforts to overcome these limitations, there remains an urgent need for a general methodology for the radiosynthesis of 18F-labelled arenes that bear electron-rich and/or sterically hindered functionalities. Herein we describe an efficient one-step labelling strategy that employs novel spirocyclic hypervalent iodine(III)-complexes to achieve regioselective radiolabelling of a broad range of non-activated, functionalized arenes and heteroarenes. These precursors are prepared in open-flasks, are stable, easily purified and readily reacted with nucleophilic [18F]fluoride. Radiofluorination was achieved in one-step by a combination of the precursor with tetraethylammonium [18F]fluoride at 120�C in DMF for 10 min. A wide range of non-activated arenes with structurally diverse functional groups, including esters, carbamates, halides, amides, nitro groups, trifluoromethyl groups, ketones, and nitrogen heterocycles, was efficiently radiolabelled in high radiochemical yields and specific activities For example, we synthesized the PET radiopharmaceutical, 5-[18F]fluorouracil which is difficult to synthesize by nucleophilic substitution reaction and was only prepared by electrophilic radiofluorination methods. In this reaction, 5-iodo-2,4-dimethoxypyrimidine was converted to the corresponding spiroiodine(III) precursor and underwent radiofluorination followed by deprotection by aqueous hydrobromic acid, to generate 5-[18F]fluorouracil in 11% uncorrected isolated radiochemical yield from dried [18F]fluoride with a specific activity of more than 0.4 Ci/�mol. This and all other isolated compounds and radiopharmaceuticals presented herein were easily automated and purified by standard isocratic HPLC conditions, lending this methodology suitable for routine radiopharmaceutical production.

Spirocyclic hypervalent iodine(III)-mediated radiofluorination as a practical method to synthesize fluorine-18 labeled non-activated aromatics

248th National Meeting (2014)

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