Phase transfer catalysts and role of reaction environment in nucleophilc radiofluorinations in automated synthesizers

Abstract

Incorporation of [18F]fluorine into PET radiotracer structure has traditionally been accomplished via nucleophilic pathways. The [18F]fluoride is generated in an aqueous solution via proton irradiation of oxygen‐18 enriched water and must to be introduced into water‐free organic solutions in order to generate reactive species. Thus nucleophilic18F‐fluorination traditionally included steps for [18F]fluoride concentration on the anion exchange resin, followed by removal of residual water via azeotropic distillation with MeCN, a time‐consuming process associated with radioactivity losses and difficult automation. To circumvent this, several adsorption/elution protocols were developed based on the minimization of water content in traditional kryptofix‐based [18F]fluoride eluents. The use of pre‐dried KOH/kryptofix solutions, tertiary alcohols, and strong organic bases was found to be effective. Advances in transition metal‐mediated SNAr approaches for radiolabeling of non‐activated aromatic substrates have prompted development of alternative techniques for reactive [18F]fluoride species generation, such as organic solutions of non‐basic alkyl ammonium and pyridinium sulfonates, etc. For radiofluorinations of iodonium salts precursors, a “minimalist” approach was introduced, avoiding the majority of pitfalls common to more complex methods. These innovations allowed the development of new time‐efficient and convenient work‐up procedures that are easily implementable in modern automated synthesizers. They will be the subject of this review.