title: Structure-activity relationships of fluorinated (E)-3-((6-methylpyridin-2-yl)ethynyl)cyclohex-2-enone-O-methyloxime (ABP688) derivatives and the discovery of a high affinity analogue as a potential candidate for imaging metabotropic glutamate recepors subtype 5 (mGluR5) with positron emission tomography (PET).
abstract: The metabotropic glutamate receptor subtype 5 (mGluR5) is recognized to be involved in numerous brain disorders. In an effort to obtain a fluorine-18 labeled analogue of the mGluR5 PET tracer [(11)C]ABP688, 13 novel ligands based on the core structure of ABP688 were synthesized. Molecules in which the methyl group at the oxime functionality of ABP688 was replaced by fluorobenzonitriles, fluoropyridines, and fluorinated oxygen containing alkyl side chains were investigated. Substituents at the oxime functionality are well tolerated and resulted in five candidates with K(i) values below 10 nM. The most promising candidate, (E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone-O-2-(2-fluoroethoxy)ethyloxime (38, K(i) = 3.8 nM), was radiolabeled with fluorine-18. Scatchard analysis of [(18)F]38 which modeled best for two sites pointed to high binding affinity (K(D1) = 0.61 +/- 0.19 nM and K(D2) = 13.73 +/- 4.69 nM) too. These data strongly suggest the further evaluation of [(18)F]38 as a candidate for imaging the mGluR5.
authors.affiliation: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences of ETH Zurich, Zurich, Switzerland.
authors.forename: Cindy A
authors.initials: CA
authors.lastname: Baumann
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
authors.forename: Sinja
authors.initials: S
authors.lastname: Johannsen
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: D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D005462:Fluorine Radioisotopes; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; C550155:3-(pyridin-2-ylethynyl)cyclohex-2-enone-O-2-(2-fluoroethoxy)ethyloxime; D000480:Alkynes; D005462:Fluorine Radioisotopes; C578937:Grm5 protein, rat; D010091:Oximes; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate