title: Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [(11)C]MADAM PET study.
abstract: BACKGROUND
  A number of serotonin receptor positron emission tomography (PET) radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment.
  
  
  OBJECTIVE
  The cross-species differential SSRI effect may be partly explained by serotonin transporter (SERT) occupancy in monkey brain being higher than is clinically relevant. We here determine SERT occupancy after single doses of escitalopram or citalopram by conducting PET measurements with [(11)C]MADAM in monkeys. Relationships between dose, plasma concentration and SERT occupancy were estimated by one-site binding analyses. Binding affinity was expressed as dose (ID50) or plasma concentration (K i) where 50 % SERT occupancy was achieved.
  
  
  RESULTS
  Estimated ID50 and K i values were 0.020 mg/kg and 9.6 nmol/L for escitalopram and 0.059 mg/kg and 9.7 nmol/L for citalopram, respectively. Obtained K i values are comparable to values reported in humans.
  
  
  CONCLUSIONS
  Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Building R5:02, SE-17176, Stockholm, Sweden. sjoerd.finnema@ki.se.|Department of Diagnostic Radiology, Yale University, New Haven, CT, USA. sjoerd.finnema@ki.se.
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Building R5:02, SE-17176, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: H. Lundbeck A/S, Neuroscience Drug Discovery Denmark, Valby, Denmark.
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.affiliation: H. Lundbeck A/S, Neuroscience Drug Discovery Denmark, Valby, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Building R5:02, SE-17176, Stockholm, Sweden.|AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology*; D005260:Female; D000882:Haplorhini; D008252:Macaca fascicularis; D049268:Positron-Emission Tomography; D011485:Protein Binding; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D015283:Citalopram; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Citalopram; Non-human primate; Occupancy; PET; Serotonin; Transporter