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

Translation of new (18)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 (18)F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful (18)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 [(18)F]fluoride of human doses of [(18)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 [(18)F]5-fluorouracil precursor. Routine production of >10 mCi doses of [(18)F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [(18)F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated (18)F-fluorination.