title: Synthesis and evaluation of [11C]MMPIP as a potential radioligand for imaging of metabotropic glutamate 7 receptor in the brain.
abstract: BACKGROUND
  Metabotropic glutamate 7 (mGlu7) receptor is a crucial target protein for the development of pharmaceuticals against central nervous system disorders. In the present study, we synthesized [11C]MMPIP, a putative radioligand for mGlu7 (binding constant KB = 30 nM), and evaluated its potential for imaging of mGlu7 via in vitro and in vivo techniques.
  
  
  METHODS
  [11C]MMPIP was synthesized by the reaction of phenol precursor 3 with [11C]CH3I. In vitro autoradiography using [11C]MMPIP was performed on rat brain sections. To determine in vitro specific binding of [11C]MMPIP with mGlu7, a blocking study was conducted by co-incubation with excess AMN082, a selective antagonist for mGlu7, or unlabeled MMPIP. Positron emission tomography (PET) studies and ex vivo metabolite analysis were carried out on rat brains.
  
  
  RESULTS
  [11C]MMPIP was obtained with two specific activity (SA) levels of average 58 (conventional) and 3,800 (high SA) GBq/μmol, respectively. High radioactive signals derived from conventional [11C]MMPIP in the in vitro autoradiography were seen in the thalamus, medulla oblongata, and striatum, corresponding with comprehensive brain distributions of mGlu7. Co-incubation with ANM082 or unlabeled MMPIP reduced the radioactive signals in the brain sections, respectively. In the PET studies with [11C]MMPIP, no specific uptake relative to mGlu7 was found in the examined brain regions.
  
  
  CONCLUSIONS
  Despite in vitro specific binding of [11C]MMPIP with mGlu7, visualization of mGlu7 in the living brain using PET was not successful. Development of new ligand candidates with higher affinity for mGlu7 is necessary.
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. zhang@nirs.go.jp.
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.forename: Kenji
authors.initials: K
authors.lastname: Furutsuka
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
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