A Transmetalation Reaction Enables the Synthesis of [ 18 F]5-Fluorouracil from [ 18 F]Fluoride for Human PET Imaging.

Translation of new F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [F]fluoride of human doses of [F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [F]5-fluorouracil precursor. Routine production of >10 mCi doses of [F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated F-fluorination.