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

Nucleophilic incorporation of [ super(18)F]F super(-) 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 super(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 [ super(18)F]fluorides from their sulfonyl chloride analogues in 1:1 mixtures of acetonitrile, THF, or tBuOH and Cs[ super(18)F]F/Cs sub(2)CO sub(3(aq.)) in a reaction time of 15min 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 [ super(18)F]fluorination (1:1:0.8 tBuOH/Cs sub(2)CO sub(3(aq. ))/pyridine) did not negatively affect yields of 3-formyl-2,4,6-trimethylbenzenesulfonyl [ super(18)F]fluoride (2) and dramatically improved the yields of 4-(prop-2-ynyloxy)benzenesulfonyl [ super(18)F]fluoride (4). The N-arylsulfonyl-4-dimethylaminopyridinium derivative of 4 (14) can be prepared and incorporates super(18)F efficiently in solutions of 100% aqueous Cs sub(2)CO sub(3) (10mgmL super(-1)). As proof-of-principle, [ super(18)F]2 was synthesised in a preparative fashion [88( plus or minus 8)% decay corrected (n=6) from start-of-synthesis] and used to radioactively label an oxyamino-modified bombesin(6-14) analogue [35( plus or minus 6)% decay corrected (n=4) from start-of-synthesis]. Total preparation time was 105-109min from start-of-synthesis. Although the super(18)F-peptide exhibited evidence of proteolytic defluorination and modification, our study is the first step in developing an aqueous, room temperature super(18)F labelling strategy. super(18)F chemistry in water at RT: A super(18)F labelling strategy for the synthesis of PET biomarkers in which arylsulfonyl chloride prosthetics are efficiently labelled in basic mixtures of aqueous [ super(18)F]F super(-) 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.