title: Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study.
abstract: Identification of a biomarker that can inform on extracellular serotonin (5-HT) levels in the brains of living humans would enable greater understanding of the way brain circuits are modulated by serotonergic neurotransmission. Substantial evidence from studies in animals and humans indicates an inverse relationship between central 5-HT tonus and 5-HT type 4 receptor (5-HT4R) density, suggesting that 5-HT4R receptor density may be a biomarker marker for 5-HT tonus. Here, we investigated whether a 3-week administration of a selective serotonin reuptake inhibitor, expected to increase brain 5-HT levels, is associated with a decline in brain 5-HT4R binding. A total of 35 healthy men were studied in a placebo-controlled, randomized, double-blind study. Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine, 40 mg per day. Brain 5-HT4R binding was quantified at baseline and at follow-up with [(11)C]SB207145 positron emission tomography (PET). Three weeks of intervention with fluoxetine was associated with a 5.2% reduction in brain 5-HT4R binding (P=0.017), whereas placebo intervention did not change 5-HT4R binding (P=0.52). Our findings are consistent with a model, wherein the 5-HT4R density adjusts to changes in the extracellular 5-HT tonus. Our data demonstrate for the first time in humans that the imaging of central 5-HT4R binding may be used as an in vivo biomarker of the central 5-HT tonus.
authors.affiliation: 1] Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark [2] Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.
authors.forename: M E
authors.initials: ME
authors.lastname: Haahr
authors.affiliation: 1] Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark [2] Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.
authors.forename: P M
authors.initials: PM
authors.lastname: Fisher
authors.affiliation: 1] Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark [2] Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.
authors.forename: C G
authors.initials: CG
authors.lastname: Jensen
authors.affiliation: 1] Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark [2] Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.
authors.forename: V G
authors.initials: VG
authors.lastname: Frokjaer
authors.affiliation: 1] Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark [2] Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.
authors.forename: B Mc
authors.initials: BM
authors.lastname: Mahon
authors.affiliation: 1] Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark [2] Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Madsen
authors.affiliation: 1] Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark [2] Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
authors.forename: W F C
authors.initials: WF
authors.lastname: Baaré
authors.affiliation: 1] Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark [2] Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Lehel
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Norremolle
authors.affiliation: 1] Imanova, Centre for Imaging Sciences, London, UK [2] Centre for Neuroscience Imaging, Institute of Psychiatry, King's College London, London, UK.
authors.forename: E A
authors.identifier: 0000000336126687
authors.initials: EA
authors.lastname: Rabiner
authors.affiliation: 1] Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark [2] Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark.
authors.forename: G M
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D004311:Double-Blind Method; D005473:Fluoxetine / Q000494:pharmacology; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010880:Piperidines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D005473:Fluoxetine; D010880:Piperidines; D044422:Receptors, Serotonin, 5-HT4; D017367:Selective Serotonin Reuptake Inhibitors; C534709:SB 207145