title: [11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in cats.
abstract: The in vivo pharmacological profile of [(11)C]-DASB, a new radioligand developed for in vivo imaging of the serotonin transporter (SERT), was evaluated in the cat brain using positron emission tomography (PET). The in vivo distribution of [(11)C]-DASB binding was consistent with the known distribution of SERT sites in the cat brain in vitro with high uptakes of radioactivity in the midbrain and thalamus, intermediate levels in striatum, and modest to low levels of radioactivity in the neocortex and cerebellum, respectively. [(11)C]-DASB binding potential (BP) values ranged from about 0.2 in the neocortex to 2.2 in the midbrain. Radioligand binding in all brain regions except cerebellum was markedly reduced following pretreatment with fluoxetine and citalopram, but was unaffected by pretreatment with GBR12909, maprotiline, and haloperidol, indicating specificity of [(11)C]-DASB binding to the SERT. Two cats were each examined using PET and [(11)C]-DASB in a longitudinal fashion (from 30 min and up to 24 days) following a single i.v. dose of: 1) fluoxetine, and 2) citalopram at different dosages. Both drugs induced similar degrees of SERT occupancy at 30 min postinjection (approximately 90%). A comparison of citalopram and fluoxetine pharmacokinetics in the same animal and at the same dosage (1 mg/kg) showed that citalopram SERT occupancy and plasma half-lives were 9 times and 14 times shorter, respectively, than those of fluoxetine and norfluoxetine. In addition, studies performed after injection of the monoamine oxidase inhibitor tranylcypromine suggested that high levels of synaptic serotonin may compete with [(11)C]-DASB for binding on the SERT. These studies indicate that [(11)C]-DASB is a suitable PET radioligand for measuring drug occupancy of the SERT in vivo and has potential for monitoring in vivo changes in serotonin levels.
authors.affiliation: PET Centre, Centre for Addiction and Mental Health and University of Toronto, Toronto, Ontario M5T 1R8, Canada. nginovart@camhpet.on.ca
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Meyer
authors.forename: Doug
authors.initials: D
authors.lastname: Hussey
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002415:Cats; D015283:Citalopram / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008376:Maprotiline / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000494:pharmacology; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods; D014191:Tranylcypromine / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D001596:Benzylamines; D002352:Carrier Proteins; D015283:Citalopram; D018492:Dopamine Antagonists; D005473:Fluoxetine; D006220:Haloperidol; D008376:Maprotiline; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D010879:Piperazines; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014191:Tranylcypromine; C461261:(1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate); C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; C036139:norfluoxetine