title: Preclinical and the first clinical studies on [11C]ITMM for mapping metabotropic glutamate receptor subtype 1 by positron emission tomography.
abstract: BACKGROUND
  Preclinical studies and first positron emission tomography (PET) imaging studies were performed using N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[(11)C]methoxy-N-methylbenzamide ([(11)C]ITMM) to map metabotropic glutamate receptor type 1 (mGluR1) in the human brain.
  
  
  METHODS
  [(11)C]ITMM was synthesized by O-methylation of the desmethyl precursor with [(11)C]methyl triflate in the presence of NaOH at room temperature. In vitro selectivity and brain distributions of [(11)C]ITMM in mice were characterized. Radiation absorbed-dose by [(11)C]ITMM in humans was calculated from mouse distribution data. Acute toxicity of ITMM at 4.72 mg/kg body weight (>74,000-fold clinical equivalent dose of [(11)C]ITMM) was evaluated. Mutagenicity of ITMM was studied by the Ames test. Clinical PET imaging of mGluR1 with [(11)C] ITMM was performed in a healthy volunteer.
  
  
  RESULTS
  ITMM had low activity for a 28-standard receptor binding profile. Regional brain uptake of [(11)C]ITMM in mice was heterogeneous and consistent with known mGluR1 distributions. The radiation absorbed-dose by [(11)C]ITMM in humans was sufficiently low for clinical use, and no acute toxicity or mutagenicity of ITMM occurred. A 90-min dynamic PET scan with [(11)C]ITMM in a healthy volunteer showed a gradual increase of radioactivity in the cerebellum. Total distribution volume of [(11)C]ITMM was highest in the cerebellum, followed by thalamus, cerebral cortex, and striatum; regional differences in brain radioactivity corresponded to the mGluR1 distribution in the brain. Peripherally, [(11)C]ITMM was stable in humans: 60% of the plasma radioactivity remained in the unchanged form for 60 min.
  
  
  CONCLUSIONS
  [(11)C] ITMM is a suitable radioligand for imaging mGluR1 in the human brain providing acceptable dosimetry and pharmacological safety at the dose required for PET.
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022, Japan. toyohara@pet.tmig.or.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Toyohara
authors.forename: Muneyuki
authors.initials: M
authors.lastname: Sakata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Oda
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishii
authors.forename: Ming Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Cristina Maria
authors.initials: CM
authors.lastname: Moriguchi Jeckel
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
mesh_terms: D000328:Adult; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000633:toxicity; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D006801:Humans; D008297:Male; D051379:Mice; D057054:Molecular Imaging; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D011874:Radiometry; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry / Q000633:toxicity; D018675:Toxicity Tests
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; C573292:N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-methoxy-N-methylbenzamide; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1