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

Abstract

Nucleophilic incorporation of [(18)F]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 (18)F-labelled biomarkers for PET chemistry. We developed a general route to prepare bifunctional 4-formyl-, 3-formyl-, 4-maleimido- and 4-oxylalkynl-arylsulfonyl [(18)F]fluorides from their sulfonyl chloride analogues in 1:1 mixtures of acetonitrile, THF, or tBuOH and Cs[(18)F]F/Cs(2)CO(3(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 [(18)F]fluorination (1:1:0.8 tBuOH/Cs(2)CO(3(aq.))/pyridine) did not negatively affect yields of 3-formyl-2,4,6-trimethylbenzenesulfonyl [(18)F]fluoride (2) and dramatically improved the yields of 4-(prop-2-ynyloxy)benzenesulfonyl [(18)F]fluoride (4). The N-arylsulfonyl-4-dimethylaminopyridinium derivative of 4 (14) can be prepared and incorporates (18)F efficiently in solutions of 100 % aqueous Cs(2)CO(3) (10 mg mL(-1)). As proof-of-principle, [(18)F]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 (18)F-peptide exhibited evidence of proteolytic defluorination and modification, our study is the first step in developing an aqueous, room temperature (18)F labelling strategy.

18F-Fluorosulfate for PET Imaging of the Sodium–Iodide Symporter: Synthesis and Biologic Evaluation In Vitro and In Vivo

“…To our knowledge, this work is the first example of imaging in vivo by PET/CT using a tracer with an S-18 F bond. The simplicity of 18 F-SO 3 F 2 synthesis, and its adequate in vivo stability, suggest that further attention should be given to "inorganic" 18 F-radiopharmaceutical synthesis (24) whereby atoms other than carbon, such as aluminum, silicon, boron, and now sulfur (25), serve as binding sites for 18 F. …”

Magnetic Droplet Microfluidics as a Platform for the Concentration of [18F]Fluoride and Radiosynthesis of Sulfonyl [18F]Fluoride

“…8 Nevertheless, our measured apparent activity was found to be lower compared to 105 GBq/μmol (2.8 Ci/μmol) that was previously reported. 7 This difference may be attributed to the fact that we did not selectively degrade the sulfonyl chloride precursor in this case with pyridine base.…”

Improved synthesis of [18F]FS-PTAD as a new tyrosine-specific prosthetic group for radiofluorination of biomolecules

“…The solubility of the precursor plays an important role to enhance the radiochemical yield. Moreover, addition of 4-dimethylaminopyridine (DMAP) leads to the formation of N-sulfonyldimethylaminopyridinum salt, which improved the labeling step and facilitating the purification of the radiofluorinated product by cartridge as described previously (Inkster et al, 2012). In our work, N-bromosuccinimide (NBS) and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in acetonitrile, were found to be the oxidizing agents of choice due to complete conversion of the [ 18 F]3 to [ 18 F]FS-PTAD ([ 18 F]4) within 5 min.…”

“…2 4-[4-(chlorosulfonyl)phenyl]urazole (2), used as precursor, was synthesized starting from the commercially available 4-phenylurazole (1) with chlorosulfonic acid at 60°C in 68% yield (Keana et al, 1983). The reference standard intermediate 4-[4-(fluorosulfonyl)phenyl]urazole (3) was prepared using the standard procedure of tetra-n-butylammonium fluoride (TBAF) in THF at room temperature (Inkster et al, 2012). The previous intermediate 3 was treated with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) to give the highly instable intermediate FS-PTAD (4) which was used without further purification for the coupling reactions with phenol (5a) and tyrosine derivatives (5b,c) to afford reference standards 6a-c.…”