Abstract

Positron Emission Tomography is a high-resolution, sensitive, functional imaging technique, which can efficiently give access to the distribution, pharmacokinetics and -dynamics of a drug in vivo and which can therefore advantageously play a key-role in both drug discovery and development. This molecular imaging technique requires the preparation of a positron-emitting radiolabelled probe or radiotracer and for this purpose, fluorine-18 is becoming, more and more often, the radionuclide of choice (adequate physical and nuclear characteristics and potential wide use and - distribution of fluorine-18-labelled radiopharmaceuticals). Considering chemical structures showing a fluoropyridinyl moiety, nucleophilic heteroaromatic substitution at the ortho-position with no-carrier-added [18F]fluoride appears today as the most efficient method for the radiosynthesis of radiotracers and radiopharmaceuticals of high specific radioactivity when compared to homoaromatic-, but also aliphatic, nucleophilic radiofluorination. Like for the aliphatic nucleophilic radiofluorinations, only a good leaving group is required (a halogen, or better a nitro- or a trimethylammonium group). There is no need for an additional strong electron-withdrawing substituent for activation of the aromatic ring such as in the homoaromatic nucleophilic radiofluorinations, except if one considers meta-fluorination. Nucleophilic heteroaromatic substitution and consequent fluorine-18 incorporation are generally performed in DMSO with the no-carrier-added, activated K[18F]F-K222 complex using conventional heating at a moderately high temperature (120-150°C) or microwave irradiation (100 Watt) for a short period of time (1-2 minutes) and often lead to high radiochemical yields. This review summarizes some of the recent applications of these nucleophilic heteroaromatic substitutions in the pyridine series and highlights its potential in the design (not seldom by hydrogen, hydroxyl or halogen replacement by fluorine) and preparation, of often drug-based, fluorine-18-labelled radiotracers and radiopharmaceuticals of high specific radioactivity for PET imaging.

Keywords: drug discovery, drug development, positron emission tomography, radiopharmaceutical, fluorine, fluoropyridine