Lafargue Anne-Elodie, Maingueneau Clémence, Bernay Benoit, Ejjoummany Abdelaziz, Perrio Cécile
CNRS, CEA, Caen Normandie University, Cyceron, Caen 14074, France.
UNICAEN, US EMerode, Proteogen Plateform, Normandie Université, Caen 14032, France.
ACS Omega. 2025 Apr 24;10(17):17983-17992. doi: 10.1021/acsomega.5c01335. eCollection 2025 May 6.
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 [F]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, [F]fluorosulfocompounds as a new class of promising hydrophilic radiophamaceuticals. Herein, we first depict a further exploration of the F-radiochemistry of sultones, including a comparative study with acyclic sulfonate esters. Propane sultones were found to be highly reactive toward [F]TBAF (tetra--butylammonium fluoride) under mild anhydrous conditions and far more reactive than acyclic analogues (mesylate and tosylate) and butane sultones. We then developed the F-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 F-radiolabeling of biopolymers under biocompatible conditions. In addition, these findings open the way to the development of innovative radiopharmaceuticals that are especially appropriate for imaging by taking advantage of the anionic sulfo group.
磺酸酯基团（如三氟甲磺酸酯、甲磺酸酯、对甲苯磺酸酯或对硝基苯磺酸酯）的脂肪族亲核取代反应是氟 -18 化学中的一个重要反应，正电子发射断层扫描（PET）临床成像中常规制备的 [F]FDG（氟代脱氧葡萄糖）的放射合成就说明了这一点。在先前的研究中，已表明环丁砜（即环状磺酸酯）的放射性氟化反应通过开环能轻松得到 [F] 氟代磺化合物，这是一类有前景的新型亲水性放射性药物。在此，我们首先描述了对环丁砜的 F 放射化学的进一步探索，包括与链状磺酸酯的对比研究。发现丙烷磺内酯在温和的无水条件下对 [F]TBAF（四丁基氟化铵）具有高反应活性，且比链状类似物（甲磺酸酯和对甲苯磺酸酯）以及丁烷磺内酯的反应活性高得多。然后，我们根据双开环策略，从双丙烷磺内酯出发，开发了蛋白质（人血清白蛋白）和糖蛋白（重组人促红细胞生成素）的 F 标记方法，该策略包括放射性氟化，随后在水性缓冲溶液中与赖氨酸残基中的 ε - 氨基进行生物共轭。总体而言，结果突出了丙烷磺内酯与链状类似物在放射性氟化方面的差异，并证实了双丙烷磺内酯作为在生物相容条件下用于生物聚合物 F 放射性标记的新型关键前体的可行性。此外，这些发现为开发特别适合成像的创新放射性药物开辟了道路，这些药物利用了阴离子磺基。
