Sultones for Radiofluorination and Bioconjugation: Fluorine-18 Labeling of Native Proteins and Glycoproteins

Aliphatic nucleophilic substitution of a sulfonate ester group (such as triflate, mesylate, tosylate, or nosylate) represents a prominent reaction in fluorine-18 chemistry, as illustrated by the radiosynthesis of [¹⁸F]FDG (fluorodeoxyglucose) routinely produced for clinical imaging by positron emission tomography (PET). In prior studies, radiofluorination of sultones (i.e., cyclic sulfonate esters) was shown to easily afford, by ring opening, [¹⁸F]fluorosulfocompounds as a new class of promising hydrophilic radiophamaceuticals. Herein, we first depict a further exploration of the ¹⁸F-radiochemistry of sultones, including a comparative study with acyclic sulfonate esters. Propane sultones were found to be highly reactive toward [¹⁸F]TBAF (tetra-n-butylammonium fluoride) under mild anhydrous conditions and far more reactive than acyclic analogues (mesylate and tosylate) and butane sultones. We then developed the ¹⁸F-labeling of protein (human serum albumin) and glycoprotein (recombinant human erythropoietin) according to a double ring opening strategy from a bispropane sultone involving radiofluorination followed by subsequent bioconjugation in aqueous buffer solution to the ε-amino group in lysine residues. Overall, the results highlight the distinction of propane sultones vs acyclic analogues for radiofluorination, and they confirm the viability of the bispropane sultone as a novel key precursor for the ¹⁸F-radiolabeling of biopolymers under biocompatible conditions. In addition, these findings open the way to the development of innovative radiopharmaceuticals that are especially appropriate for in vivo imaging by taking advantage of the anionic sulfo group.