2-[18F]fluoropyridines by no-carrier-added nucleophilic aromatic substitution with [18F]FK-K222—a comparative study

Abstract

The scope of the nucleophilic aromatic substitution reaction of 2-substituted pyridines with no-carrier-added [18F]fluoride ion (half life: 110 minutes) as its [18F]FK-K222 activated complex, has been evaluated via the radiosynthesis of 2-[18F]fluoropyridine, chosen as a model reaction. The parameters studied include the influence of the leaving group in the 2 position of the pyridine ring, the quantity of the precursor used, the type of activation (conventional heating, micro- & ultrasonic wave irradiations), the solvent, the temperature and the duration of the reaction. Concerning the influence of the leaving group, 2-chloro- and 2-bromopyridine gave moderate to good fluorine-18 incorporation yields while 2-nitro- and especially 2-trimethylammonium pyridine gave excellent incorporation yields. Noteworthy, 2-iodopyridine was almost unreactive. As expected, the incorporation yield increased with the quantity of precursor used: high yields were observed from about 7 μmol of precursor. Using conventional heating and regardless of the substituent in the 2 position of the pyridine ring, the best yields for the radiosynthesis of 2-[18F]fluoropyridine were obtained when the temperature of the reaction was 180°C and the solvent DMSO. The yields for the 2-nitro- and the 2-trimethylammonium pyridine precursors were 77% and 88% respectively, after only 5 minutes of reaction and were similar to those observed at 150°C for longer reaction times. At 120°C, neither the 2-chloro- nor the 2-bromopyridine gave any incorporation. Using microwave irradiations, excellent incorporation yields (96%) were observed for the 2-trimethylammonium pyridine from 1 minute of reaction at 100 Watt in DMSO. Concerning the 2-chloro-, 2-bromo and 2-nitropyridine, the use of 100 Watt microwave irradiations for 2 minutes gave yields comparable to those obtained for 10 minutes of conventional heating at 180°C, 22%, 71% and 88% respectively. No incorporation at all of the radioactivity could be detected when ultrasonic waves were applied, even with long reaction time and high power. Copyright © 1999 John Wiley & Sons, Ltd.