Sulfonyl fluoride-based prosthetic compounds as potential 18F labelling agents.
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.
Department of Nuclear Medicine, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia, Canada. jamesi@triumf.ca
James A H
JA
Inkster
Kate
K
Liu
Samia
S
Ait-Mohand
Paul
P
Schaffer
Brigitte
B
Guérin
Thomas J
TJ
Ruth
Tim
T
Storr
D000818:Animals; D001839:Bombesin / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000302:isolation & purification; D054879:Halogenation; D007553:Isotope Labeling / Q000379:methods*; D051379:Mice; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000302:isolation & purification; D013441:Sulfinic Acids / Q000737:chemistry* / Q000302:isolation & purification; D014867:Water
D005462:Fluorine Radioisotopes; D011725:Pyridines; D019275:Radiopharmaceuticals; D013441:Sulfinic Acids; D014867:Water; C048899:sulfuryl fluoride; C044255:sulfonyl chloride; C023666:pyridine; D001839:Bombesin