Syntheses and pharmacological characterization of novel thiazole derivatives as potential mGluR5 PET ligands.
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.
Baumann
Cindy A
CA
Center for Radiopharmaceutical Sciences, ETH Zurich (Swiss Federal Institute of Technology), Zurich, Switzerland.
Mu
Linjing
L
Wertli
Nicole
N
Krämer
Stefanie D
SD
Honer
Michael
M
Schubiger
Pius A
PA
Ametamey
Simon M
SM
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*
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