title: Syntheses and pharmacological characterization of novel thiazole derivatives as potential mGluR5 PET ligands.
abstract: Four novel thiazole containing ABP688 derivatives were synthesized and evaluated for their binding affinity towards the metabotropic glutamate receptor subtype 5 (mGluR5). (E)-3-((2-(Fluoromethyl)thiazol-4-yl)ethynyl)cyclohex-2-enone O-methyl oxime (FTECMO), the ligand with the highest binding affinity (K(i)=5.5+/-1.1 nM), was labeled with fluorine-18. [(18)F]-FTECMO displayed optimal lipophilicity (log D(pH7.4)=1.6+/-0.2) and high stability in rat and human plasma as well as sufficient stability in rat liver microsomes. In vitro autoradiography with [(18)F]-FTECMO revealed a heterogeneous and displaceable binding in mGluR5-rich brain regions. PET imaging with [(18)F]-FTECMO in Wistar rats, however, showed low brain uptake. Uptake of radioactivity into the skull was observed suggesting in vivo defluorination. Thus, although [(18)F]-FTECMO is an excellent ligand for the detection of mGluR5 in vitro, its in vivo characteristics are not optimal for the imaging of mGluR5 in rats in vivo.
authors.affiliation: Center for Radiopharmaceutical Sciences, ETH Zurich (Swiss Federal Institute of Technology), Zurich, Switzerland.
authors.forename: Cindy A
authors.initials: CA
authors.lastname: Baumann
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
authors.forename: Nicole
authors.initials: N
authors.lastname: Wertli
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Pius A
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011859:Radiography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D008024:Ligands; D019275:Radiopharmaceuticals; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles