title: PET measurement of serotonin transporter occupancy: a comparison of escitalopram and citalopram.
abstract: The selective serotonin reuptake inhibitor (SSRI) citalopram (R,S-citalopram) is a racemic compound of two enantiomers. On the basis of in-vitro studies, inhibition of the human serotonin transporter (5-HTT) is achieved by the S-enantiomer (S-citalopram or escitalopram). The aim of the present PET study was to compare 5-HTT occupancy after single equimolar doses (with respect to S-enantiomer) in humans in vivo using R,S-citalopram (20 mg) and S-citalopram (10 mg) using PET and the radioligand [(11)C]MADAM. The design was a single-dose, double-blind, two-way crossover study in eight healthy male subjects. The 5-HTT binding potential at baseline and after single doses of study drugs was used to calculate 5-HTT occupancy in seven brain regions. Serum concentrations of the study drugs were determined in order to calculate the apparent inhibition constant (K(i),(app)), a secondary parameter of interest for the comparison. In all brain regions examined, occupancy was numerically higher after treatment with R,S-citalopram [66+/-19% to 78+/-17% (mean+/-s.d.) depending on the region] than after S-citalopram (59+/-15% to 69+/-13%; overall comparison: F=14.8, d.f.=1, 90, p<0.001). In line with this the apparent inhibition constant was significantly lower for R,S-citalopram than for S-citalopram (overall comparison: F=6.7, d.f.=1, 90, p<0.05). The small but significant difference in occupancy and K(i),(app) found between R,S-citalopram and S-citalopram suggests that not only S-citalopram but also R-citalopram to some degree occupies the 5-HTT in the human brain in vivo.
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden. johan.lundberg@ki.se
authors.forename: Johan
authors.initials: J
authors.lastname: Lundberg
authors.forename: Jacob Strøyer
authors.initials: JS
authors.lastname: Christophersen
authors.forename: Kamilla Buchberg
authors.initials: KB
authors.lastname: Petersen
authors.forename: Henrik
authors.initials: H
authors.lastname: Loft
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D001596:Benzylamines; D001921:Brain / Q000000981:diagnostic imaging*; D015283:Citalopram / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D001596:Benzylamines; D015283:Citalopram; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C470437:N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine