title: Synthesis and evaluation of 4-halogeno-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-[11C]methylbenzamide for imaging of metabotropic glutamate 1 receptor in melanoma.
abstract: Metabotropic glutamate 1 (mGlu1) receptor is found not only in the brain but also in melanomas and breast cancers. mGlu1 is a promising target for molecular imaging-based diagnosis and treatment of melanoma because its overexpression induces melanocyte carcinogenesis. Here we developed three PET tracers: 4-halogeno-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol- 2-yl]-N-[(11)C]methylbenzamide ([(11)C]4-6), which exhibited high uptake in target tumor and decreased uptake in nontarget brain tissues. In vitro binding assay indicated high to moderate binding affinities of 4-6 (Ki, 22-143 nM) for mGlu1 receptor. In vivo biodistribution studies in mice implanted with B16F10 melanoma cells confirmed high radioactive uptake in tumor and low uptake in blood, skin, and muscles. Inhibition of mGlu1 receptor using an mGlu1-selective ligand led to reduced radioactive uptake in the tumor. [(11)C]6 displayed the highest ratio of uptake between tumor and nontarget tissue and may prove useful as a PET tracer for mGlu1 imaging in melanoma.
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: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimoda
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.forename: Yiding
authors.initials: Y
authors.lastname: Zhang
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008545:Melanoma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057054:Molecular Imaging; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; C573292:N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-methoxy-N-methylbenzamide; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1