Sulfonyl Fluoride-Based Prosthetic Compounds as Potential 18F Labelling Agents

• Published in: Chemistry : a European journal Vol. 18; no. 35; pp. 11079 - 11087
• Main Authors: Inkster, James A. H., Liu, Kate, Ait-Mohand, Samia, Schaffer, Paul, Guérin, Brigitte, Ruth, Thomas J., Storr, Tim
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 27-08-2012; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: acylation; Animals; Bombesin - chemistry; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; fluorine; Fluorine Radioisotopes - chemistry; Fluorine Radioisotopes - isolation & purification; Halogenation; Isotope Labeling - methods; Mice; Molecular Structure; peptides; Positron-Emission Tomography; Pyridines - chemistry; radiopharmaceuticals; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - isolation & purification; Sulfinic Acids - chemistry; Sulfinic Acids - isolation & purification; sulfonyl fluorides; Water
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201103450

Nucleophilic incorporation of [18F]F− under aqueous conditions holds several advantages in radiopharmaceutical development, especially with the advent of complex biological pharmacophores. Sulfonyl fluorides can be prepared in water at room temperature, yet they have not been assayed as a potential means to 18F‐labelled biomarkers for PET chemistry. We developed a general route to prepare bifunctional 4‐formyl‐, 3‐formyl‐, 4‐maleimido‐ and 4‐oxylalkynl‐arylsulfonyl [18F]fluorides from their sulfonyl chloride analogues in 1:1 mixtures of acetonitrile, THF, or tBuOH and Cs[18F]F/Cs2CO3(aq.) in a reaction time of 15 min at room temperature. With the exception of 4‐N‐maleimide‐benzenesulfonyl fluoride (3), pyridine could be used to simplify radiotracer purification by selectively degrading the precursor without significantly affecting observed yields. The addition of pyridine at the start of [18F]fluorination (1:1:0.8 tBuOH/Cs2CO3(aq.)/pyridine) did not negatively affect yields of 3‐formyl‐2,4,6‐trimethylbenzenesulfonyl [18F]fluoride (2) and dramatically improved the yields of 4‐(prop‐2‐ynyloxy)benzenesulfonyl [18F]fluoride (4). The N‐arylsulfonyl‐4‐dimethylaminopyridinium derivative of 4 (14) can be prepared and incorporates 18F efficiently in solutions of 100 % aqueous Cs2CO3 (10 mg mL−1). As proof‐of‐principle, [18F]2 was synthesised in a preparative fashion [88(±8) % decay corrected (n=6) from start‐of‐synthesis] and used to radioactively label an oxyamino‐modified bombesin(6–14) analogue [35(±6) % decay corrected (n=4) from start‐of‐synthesis]. Total preparation time was 105–109 min from start‐of‐synthesis. Although the 18F‐peptide exhibited evidence of proteolytic defluorination and modification, our study is the first step in developing an aqueous, room temperature 18F labelling strategy.
18F chemistry in water at RT: A 18F labelling strategy for the synthesis of PET biomarkers in which arylsulfonyl chloride prosthetics are efficiently labelled in basic mixtures of aqueous [18F]F− and organic solvent at room temperature (see scheme) has been developed. Pyridine simultaneously catalyses halogen exchange while degrading the precursor, and some N‐sulfonylated DMAP salts can be prepared and fluorinated with ease.