2-[F-18]fluoropyridines by no-carrier-added nucleophilic aromatic substitution with [F-18]FK-K-222 - A comparative study

The scope of the nucleophilic aromatic substitution reaction of 2-substitut ed pyridines with no-carrier-added [F-18]fluoride ion (half life:110 minute s) as its [F-18]FK-K-222 activated complex, has been evaluated via the radi osynthesis of 2-[F-18]fluoropyridine, chosen as a model reaction. The param eters 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 activ ation (conventional heating, micro- & ultrasonic wave irradiations), the so lvent, the temperature and the duration of the reaction. Concerning the inf luence of the leaving group, 2-chloro- and 2-bromopyridine gave moderate to good fluorine-ls incorporation yields while 2-nitro- and especially 2-trim ethylammonium pyridine gave excellent incorporation yields. Noteworthy, 2-i odopyridine was almost unreactive. As expected, the incorporation yield inc reased with the quantity of precursor used : high yields were observed from about 7 mu mol 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-[F-18]fluoropyridine were obtained when the temper ature of the reaction was 180 degrees C and the solvent DMSO. The yields fo r the 2-nitro- and the 2-trimethylammonium pyridine precursors were 77% and 88% respectively, after only 5 minutes of reaction and were similar to tho se observed at 150 degrees C for longer reaction times. At 120 degrees C, n either 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 th ose obtained for 10 minutes of conventional heating at 180 degrees C, 22%, 71% and 88% respectively. No incorporation at all of the radioactivity coul d be detected when ultrasonic waves were applied, even with long reaction t ime and high power.