Journal
JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS
Volume 49, Issue 4, Pages 345-356Publisher
JOHN WILEY & SONS LTD
DOI: 10.1002/jlcr.1049
Keywords
fluorine-18; fluoropyridine; no-carrier-added nucleophilic aromatic substitution; meta-position; Hofmann rearrangement
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A one-pot radiosynthesis method to prepare the new fluorine-18-labelled fluoropyridine derivatives 5-[F-18]fluoro-2-pyridinamine and 6-[F-18]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[F-18]F-K-222 in DMSO at 150-180 degrees C. The [F-18]fluoride incorporation yields ranged from 67 to 98% for all studied precursor molecules. It is remarkable that 5-bromo-2-pyridinecarbonitrile gave almost quantitative [F-18]fluoride incorporation at the meta-position (5-position) of the pyridine ring after only 5 min of heating at 150 degrees C. After base-catalysed hydrolysis of the [F-18]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-[F-18]fluoro-2-pyridinamine and 6-[F-18]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-[F-18]fluoro-2-pyridinamine is one of very few examples demonstrating the feasibility of nucleophilic meta-[F-18]fluorination of a pyridine derivative. Both 5-[F-18]fluoro-2-pyridinamine and 6-[F-18]fluoro-2-pyridinamine are new potentially useful radiolabelled synthons for radiopharmaceutical chemistry. Copyright (c) 2006 John Wiley & Sons, Ltd.
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