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-<i>n</i>-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 <i>in vivo</i> imaging by taking advantage of the anionic sulfo group.