Synthesis of fluorine-18-labelled 5- and 6-fluoro-2-pyridinamine

A one-pot radiosynthesis method to prepare the new fluorine-18-labelled fluoropyridine derivatives 5-[18F]fluoro-2-pyridinamine and 6-[18F]fluoro-2-pyridinamine in two to three reaction steps was developed. The first step consisted of no-carrier-added nucleophilic aromatic substitution of commercially available halogen-substituted 2-pyridinecarboxamide or 2-pyridinecarbonitrile derivatives with K[18F]F-K222 in DMSO at 150–180°C. The [18F]fluoride incorporation yields ranged from 67 to 98% for all studied precursor molecules. It is remarkable that 5-bromo-2-pyridinecarbonitrile gave almost quantitative [18F]fluoride incorporation at the meta-position (5-position) of the pyridine ring after only 5 min of heating at 150°C. After base-catalysed hydrolysis of the [18F]fluorinated pyridinecarbonitriles into their corresponding carboxamides, the latter were transformed in a Hofmann-type rearrangement reaction into the respective amines by treatment of crude reaction mixtures with bromine and aqueous base (20–30% conversion yield). Reaction mixtures were purified by reversed-phase semipreparative HPLC followed by strong cation exchange solid-phase extraction to afford 5-[18F]fluoro-2-pyridinamine and 6-[18F]fluoro-2-pyridinamine in non-decay-corrected radiochemical yields of 6–10% in a total synthesis time of 83–112 min. The preparation of 5-[18F]fluoro-2-pyridinamine is one of very few examples demonstrating the feasibility of nucleophilic meta-[18F]fluorination of a pyridine derivative. Both 5-[18F]fluoro-2-pyridinamine and 6-[18F]fluoro-2-pyridinamine are new potentially useful radiolabelled synthons for radiopharmaceutical chemistry. Copyright © 2006 John Wiley & Sons, Ltd.