Synthesis and Simple ~(18)F-Labeling of 3-Fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile as a High Affinity Radioligand for Imaging Monkey Brain Metabotropic Glutamate Subtype-5 Receptors with Positron Emission Tomography

摘要

2-Fluoromethyl analogs of (3-[(2-methyl-1,3-thiazol-4yl)ethynyl]pyridine) were synthesized as potential ligands for metabotropic glutamate subtype-5 receptors (mGluR5s). One of these, namely, 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile (3), was found to have exceptionally high affinity (IC_(50) = 36 pM) and potency in a phosphoinositol hydrolysis assay (IC_(50) = 0.714 pM) for mGluR5. Compound 3 was labeled with fluorine-18 (t_(1/2) = 109.7 min) in high radiochemical yield (87%) by treatment of its synthesized bromomethyl analog (17) with [~(18)F]fluoride ion and its radioligand behavior was assessed with positron emission tomography (PET). Following intravenous injection of [~(18)F]3 into rhesus monkey, radioactivity was avidly taken up into brain with high uptake in mGluR5 receptor-rich regions such as striata. [~(18)F]3 was stable in monkey plasma and human whole blood in vitro and in monkey and human brain homogenates. In monkey in vivo, a single polar radiometabolite of [~(18)F]3 appeared rapidly in plasma. [~(18)F]3 merits further evaluation as a PET radioligand for mGluR5 in human subjects.