An Investigation into the In Vitro Metabolic Stability of Aryl Sulfonyl Fluorides for their Application in Medicinal Chemistry and Radiochemistry.

Abstract

Molecules that feature a sulfonyl fluoride (SO2F) moiety have been gaining increasing interest due to their unique reactivity and potential applications in synthetic chemistry, medicinal chemistry, and other biological uses. A particular interest is towards 18F-radiochemistry where sulfonyl fluorides can be used as a method to radiolabel biomolecules or can be used as radiofluoride relay reagents that facilitate radiolabeling of other molecules. The low metabolic stability of sulfonyl fluoride S-F bonds, however, presents an issue and limits the applicability of sulfonyl fluorides. The aim of this work was to increase understanding of what features contribute to the metabolic instability of the S-F bond in model aryl sulfonyl fluorides and identify approaches to increasing sulfonyl fluoride stability for 18F-radiochemistry and other medicinal, synthetic chemistry and biological applications. To undertake this, 14 model aryl sulfonyl fluorides compounds with varying functional groups and substitution patterns were investigated, and their stabilities were examined in various media, including phosphate-buffered saline and rat serum as a model for biological conditions. The results indicate that both electronic and steric factors affect the stability of the S-F bond, with the 2,4,6-trisubstituted model aryl sulfonyl fluorides examined displaying the highest in vitro metabolic stability.