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.

In Vivo Radiotracer Imaging

“…Nucleophilic substitutions are then performed in an aprotic polar solvent under alkaline conditions, either on a suitable direct precursor of the target molecule (one step procedure) or on a indirect precursor followed by one or more chemical steps leading to the target radiotracer. [ More recently, the field of aromatic nucleophilic substitutions with [ 18 F]fluoride has been extended to heterocyclic chemical structures bearing a fluoropyridinyl moiety (Dolci et al, 1999). Similar to the aliphatic nucleophilic radiofluorinations, only a good leaving group is required (a halogen, or better a nitroor a trimethylammonium group), and, except if one considers meta-fluorination, there is no need for an additional strong electron-withdrawing substituent for activation of the aromatic ring such as in the homoaromatic nucleophilic radiofluorinations.…”

Quinuclidine and DABCO Enhance the Radiofluorination of 5‐Substituted 2‐Halopyridines

“…Reliable radiosyntheses of [ 18 F]2‐fluoropyridyl compounds from NCA [ 18 F]fluoride ion are based on aromatic nucleophilic substitution of good leaving groups . The effectiveness of the leaving group in radiofluorination follows the order: halide (Cl or Br) < nitro < trimethylammonium , .…”

No-carrier-added [18F]fluoroarenes from the radiofluorination of diaryl sulfoxides

“…4 This method can also be used to prepare 18 F-labeled heteroarenes, such as 2-[ 18 F]fluoropyridines and 4-[ 18 F]fluoropyridines. 5 Moreover, the radiofluorination of diaryliodonium salts has now been shown to be effective to label homoarenes and pyridines in any desirable position, irrespective of needs for electron-withdrawing groups. 6,7 This method is now finding applications for preparing otherwise difficult to access radiotracers.…”