title: Synthesis and evaluation of radioiodinated (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter.
abstract: OBJECTIVE
  Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT.
  
  
  METHODS
  (S,S)-(123/125)I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of (3)H-nisoxetine and (S,S)-(125)I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-(125)I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-(123)I-IPBM were carried out in the common marmoset.
  
  
  RESULTS
  (S,S)-(125)I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-(125)I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-(125)I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-(123)I-IPBM allowed brain NET imaging in the common marmoset with SPECT.
  
  
  CONCLUSIONS
  These results suggest that (S,S)-(123)I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanegawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kiyono
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Taku
authors.initials: T
authors.lastname: Sugita
authors.forename: Satomi
authors.initials: S
authors.lastname: Kajiyama
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kawashima
authors.forename: Masashi
authors.initials: M
authors.lastname: Ueda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D007553:Isotope Labeling; D008297:Male; D008657:Metabolic Clearance Rate; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics*; D009928:Organ Specificity; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C515866:2-(alpha-(2-iodophenoxy)benzyl)morpholine; D009025:Morpholines; D019275:Radiopharmaceuticals; D011941:Receptors, Adrenergic