title: In vivo evaluation of a new ¹⁸F-labeled PET ligand, [¹⁸F]FEBU, for the imaging of I₂-imidazoline receptors.
abstract: BACKGROUND
  The functions of I₂-imidazoline receptors (I₂Rs) are unknown, but evidence exists for their involvement in various neuropsychiatric disorders. Although a few positron emission tomography (PET) I₂R ligands have been developed, of which [(11)C]FTIMD and [(11)C]BU99008 were evaluated as PET I₂R imaging ligands in monkeys, no human PET imaging study using an I₂R-selective PET ligand has been conducted yet. Thus, we synthesized an (18)F-labeled I₂R-selective ligand (BU99018 or FEBU, Ki for I₂Rs=2.6 nM), and evaluated its application using rodents in PET imaging in vivo toward the development of a clinically-useful I₂R PET imaging ligand.
  
  
  METHODS
  [(18)F]FEBU was synthesized by the reaction of its precursor and [(18)F]fluoroethyl bromide. A biodistribution and brain PET study were conducted in mice and rats respectively.
  
  
  RESULTS
  [(18)F]FEBU was successfully synthesized yielding a radioactivity suitable for injection (10.1 ± 5.3% at the end of the irradiation (n=10) based on (18)F(-)). The specific activity at end of synthesis (EOS) was 40-147 TBq/mmol (n=10). The radiochemical purity was >99% at EOS and remained >99% for 90 min after EOS. In mice brain uptake was relatively high. In the blocking study with the co-injection of the high-affinity I₂R ligand BU224 (1 mg/kg b.w.) brain uptake was significantly decreased 30 min post-injection. In the PET studies the radioactivity was highly accumulated in the I₂R-rich hypothalamus. Pretreatment with BU224 (1 mg/kg b.w.) significantly decreased the radioactivity in the hypothalamus to 23% of that of the control from 60 to 90 min post-injection.
  
  
  CONCLUSIONS
  [(18)F]FEBU was sufficiently stable as a PET ligand and had a relatively high specific binding affinity for I₂Rs in rats and mice.
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.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimoda
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.affiliation: Biophysics Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Wakizaka
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan; SHI Accelerator Service Ltd., Tokyo 141-0032, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kurihara
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan; SHI Accelerator Service Ltd., Tokyo 141-0032, Japan.
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan; SHI Accelerator Service Ltd., Tokyo 141-0032, Japan.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D004355:Drug Stability; D054755:Imidazoline Receptors / Q000378:metabolism*; D048288:Imidazolines / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D007211:Indoles / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats; D014018:Tissue Distribution
chemical_list: C000604642:BU99018; D054755:Imidazoline Receptors; D048288:Imidazolines; D007211:Indoles; D008024:Ligands; C487767:imidazoline receptor 2
keywords: BU99018; I(2); Imidazoline receptors; PET; [(18)F]FEBU