title: Development of N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[11C]methylbenzamide for positron emission tomography imaging of metabotropic glutamate 1 receptor in monkey brain.
abstract: Three novel 4-substituted benzamides have been synthesized as potential ligands for the positron emission tomography (PET) imaging of metabotropic glutamate 1 (mGlu1) receptor in the brain. Of these compounds, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N,4-dimethylbenzamide (4) exhibited the highest binding affinity (K(i) = 13.6 nM) for mGlu1 and was subsequently labeled with carbon-11. In vitro autoradiography using rat brain sections showed that [(11)C]4 binding was consistent with the distribution of mGlu1, with high specific binding in the cerebellum and thalamus. PET studies with [(11)C]4 in monkey showed a high brain uptake and a kinetic profile suitable for quantitative analysis. Pretreatment with a mGlu1-selective ligand 16 largely decreased the brain uptake, indicating high in vivo specific binding of [(11)C]4 to mGlu1. In metabolite analysis, only unchanged [(11)C]4 was found in the brain. [(11)C]4 is a useful PET ligand for the imaging and quantitative analysis of mGlu1 in monkey brain and merits further evaluation in humans.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagai
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; C573292:N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-methoxy-N-methylbenzamide; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1