title: NET occupancy by clomipramine and its active metabolite, desmethylclomipramine, in non-human primates in vivo.
abstract: BACKGROUND
  Norepinephrine transporter (NET) is one of the key targets for antidepressants such as combined serotonin and norepinephrine reuptake inhibitors as well as some of the tricyclic antidepressants. Clomipramine, a tricyclic antidepressant, has been reported to have an active metabolite, desmethylclomipramine, which has high affinity for NET in vitro. However, the NET occupancy of clomipramine and desmethylclomipramine has not fully been evaluated in vivo.
  
  
  OBJECTIVE
  In this positron emission tomography (PET) study, we investigate NET occupancy by clomipramine and desmethylclomipramine, respectively, in non-human primates with a selective radioligand for NET, (S,S)-[(18)F]FMeNER-D(2).
  
  
  METHODS
  PET measurements were performed with (S,S)-[(18)F]FMeNER-D(2) at baseline and after the intravenous administration of clomipramine and desmethylclomipramine, respectively. NET binding was calculated with the simplified reference tissue model using the caudate as reference region. NET occupancy was calculated as the difference in NET binding between the baseline and pretreatment condition. The relationship between NET occupancy and dose/plasma concentration was evaluated using hyperbolic functions.
  
  
  RESULTS
  NET occupancy by both clomipramine and desmethylclomipramine increased in a dose and plasma concentration-dependent manner. The mean Kd values, expressed as the dose or plasma concentration at which 50% of NET was occupied, were 0.44 mg/kg and 24.5 ng/ml for clomipramine and 0.11 mg/kg and 4.4 ng/ml for desmethylclomipramine.
  
  
  CONCLUSIONS
  Not only desmethylclomipramine but also clomipramine was demonstrated to occupy NET in the non-human primate in vivo. It can thus be assumed that NET occupancy during clinical treatment with clomipramine is a combined effect of unchanged clomipramine and its main metabolite desmethylclomipramine.
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, 171 76, Stockholm, Sweden. akihiro.takano@ki.se
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.forename: Sangram
authors.initials: S
authors.lastname: Nag
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D002997:Clomipramine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis; D008297:Male; D009025:Morpholines / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding
chemical_list: C506462:2-(alpha-(2-fluoromethoxyphenoxy)benzyl)morpholine; D000929:Antidepressive Agents, Tricyclic; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; C012273:desmethylclomipramine; D002997:Clomipramine