title: Binding potential of (E)-[¹¹C]ABP688 to metabotropic glutamate receptor subtype 5 is decreased by the inclusion of its ¹¹C-labelled Z-isomer.
abstract: BACKGROUND
  [(11)C]ABP688 is a promising positron emission tomography (PET) ligand for imaging of metabotropic glutamate receptor subtype 5 (mGlu5 receptor). Of the two geometric isomers of ABP688, (E)-ABP688 has a greater affinity towards mGlu5 receptors than (Z)-ABP688. Therefore, a high ratio of E-isomer is required when using [(11)C]ABP688 as a PET probe for imaging and quantification of mGlu5 receptors. The aim of this study was to evaluate the effect (Z)-[(11)C]ABP688 on the synthesis of [(11)C]ABP688 to be used for binding (E)-[(11)C]ABP688 in the brain.
  
  
  METHODS
  We synthesized and separated (E)- and (Z)-[(11)C]ABP688 by purification using an improved preparative high-performance liquid chromatography (HPLC) method equipped with a COSMOSIL Cholester column. We performed an in vitro binding assay in rat brain homogenates and PET studies of the rat brains using (E)- and (Z)-[(11)C]ABP688.
  
  
  RESULTS
  (E)- and (Z)-[(11)C]ABP688 were successfully obtained with suitable radioactivity for application. In the in vitro assay, the Kd value of (E)-[(11)C]ABP688 (5.7 nmol/L) was higher than that of (Z)-[(11)C]ABP688 (140 nmol/L). In the PET study of the rat brain, high radioactivity after injection of (E)-[(11)C]ABP688 was observed in regions rich in mGlu5 receptors such as the striatum and hippocampus. In contrast, after injection of (Z)-[(11)C]ABP688, radioactivity did not accumulate in the brain. Furthermore, BPND in the striatum and hippocampus was highly correlated (R(2) = 0.99) with the percentage of (E)-[(11)C]ABP688 of the total radioactivity of (E)- and (Z)-[(11)C]ABP688 in the injection.
  
  
  CONCLUSIONS
  We demonstrated that including (Z)-[(11)C]ABP688 in the [(11)C]ABP688 injection can decrease BPND in regions rich in mGlu5 receptors. Routine production of (E)-[(11)C]ABP688 will be helpful for imaging and quantification of mGlu5 receptors in clinical studies.
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan. Electronic address: kawamur@nirs.go.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.forename: Kenji
authors.initials: K
authors.lastname: Furutsuka
authors.forename: Makoto
authors.initials: M
authors.lastname: Takei
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Wakizaka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.forename: Kaori
authors.initials: K
authors.lastname: Kariya
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimoda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Hayashi
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D008297:Male; D010091:Oximes / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011725:Pyridines / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; D002250:Carbon Radioisotopes; D010091:Oximes; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5
keywords: (11)C; (E)-ABP688; (Z)-ABP688; Metabotropic glutamate receptor subtype 5; Positron emission tomography