Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 50, Issue 14, Pages 3256-3266Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm0701268
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- Intramural NIH HHS Funding Source: Medline
- NIMH NIH HHS [N01MH32004] Funding Source: Medline
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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 (IC50 = 36 pM) and potency in a phosphoinositol hydrolysis assay (IC50 = 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 [F-18]fluoride ion and its radioligand behavior was assessed with positron emission tomography (PET). Following intravenous injection of [F-18]3 into rhesus monkey, radioactivity was avidly taken up into brain with high uptake in mGluR5 receptor-rich regions such as striata. [F-18]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 [F-18]3 appeared rapidly in plasma. [F-18]3 merits further evaluation as a PET radioligand for mGluR5 in human subjects.
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