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

Translation of new F-18-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-18-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful F-18-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-18]fluoride of human doses of [F-18]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel 6-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [F-18]5-fluorouracil precursor. Routine production of >10 mCi doses of [F-18]5-fluorouracil was accomplished with a new instrument for azeotrope-free [F-18]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated F-18-fluorination.