18F-labelled PET radiotracer synthesis
18F-labelled molecules are frequently used for PET because of the advantageous properties of 18F in comparison with other non-metallic radioisotopes. Direct fluorination of electron-rich aromatics with a nucleophilic source of 18F-Fluoride is a well-recognised problem in 18F-radiochemistry. The EU-funded OXIFLU (Oxidative fluorination with [18F]fluoride - new radiochemistry for PET imaging) project aimed to find a solution to this problem. The project tested an alternative approach to synthesise the two high value tracers used for imaging of the dopaminergic system. The main concept was to perform the nucleophilic fluorination of electron rich aromatics with fluoride using a so-called "substrate umpolung" approach. Under oxidative conditions, the reactivity profile of the substrate can be reverted from a nucleophilic to an electrophilic entity (umpolung), thereby allowing for nucleophilic 18F-labelling. The project used oxidative fluorination protocols to synthesise two notoriously difficult to produce compounds, using currently available radiochemistry: 6-[18F]Fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA) and 6-[18F]Fluoro-L-meta-tyrosine ([18F]FMT). The use of a microfluidic reactor allowed the reactions to be performed on a smaller scale, while ensuring good control of stoichiometry and constant flow. The compounds were successfully synthesised but the radiochemical yield was low, indicating the need for more extensive studies for future radiolabelling. OXIFLU also applied oxidative fluorination protocols to the synthesis of cyclic amides and sulphonamides. The 4-fluoroaniline motif, present in many biologically active molecules was used as a prosthetic group to introduce fluorine into larger molecules. The reaction conditions for the oxidative fluorination were optimised for each substrate. With the optimal non-radiochemical fluorination protocol in hand, the labelling of indolin-2-one was attempted, producing encouraging yield in first attempts. Availability of robust synthetic routes to produce complex labelled molecules ultimately determines the applications of PET. The results of OXIFLU were promising and warrant further studies.
Keywords
Oxidative fluorination, PET, [18F], fluoride, labelling, cyclic amide, sulphoamide