Enzymatic C-18F bond formation, a new tool for PET

Fluorine is an important substituent in products for medicinal and pharmaceutical applications. All novel drugs, including fluorinated drugs, are now required by the FDA and other international regulatory bodies to be subjected to positron emission distribution analysis in animal models before they can be licensed. Positron emission tomography (PET) is increasingly used as a diagnostic technique for cancer and neurological disorders and concomitantly, PET research is a growing field. Novel methods for the incorporation of short lived positron emitting isotopes (e.g. 18F t 1/2 = 110 min) are a strong demand. This research project aims to explore the application of an enzyme - the fluorinase (E.C. 2.5.1.63), the first ever identified with the capacity to form C-F bonds - for the incorporation of 18F-fluoride into biochemicals. Although a number of purely chemical means for fluorination have been investigated, none of them operate under mild conditions in a (chemo)selective way. The fluorinase was demonstrated to transfer 18F-fluoride ion generated by the cyclotron and convert it into organic [18]- fluorine. The goal of the project is accordingly to develop coupled enzyme reactions (biotransformations) using the fluorinase and then a second (or third) enzyme to prepare a diversity of [18]-fluorine labelled products using the fluorinase as the C-F bond forming catalyst. Initially, a `purine base swapping` will be pursued by coupling the fluorinase to a nucleotide phosphorylase to enzymatically alter the base moiety of the nucleoside. Alternatively to this follow up approach, the use of chemically modified substrates will amplify the current knowledge of the substrate specificity of the fluorinase. It is envisaged that a diversity of radiolabelled nucleosides and ribose sugar analogues can be thus prepared in cooperation with GSK (PET-Technologies). Most PET applications are in the cancer and neurological fields and these classes of compounds are directly relevant in that respect. We feel that there could be a short lead time between this research and diagnostic/clinical applications.