Abstract
Vortioxetine (Lu AA21004) is a new potential substance for the treatment of anxiety and mood disorders. It has high affinity for the 5-HT transporter (5-HTT) and moderate affinity for the 5-HT1A receptor in vitro. Positron emission tomography (PET) has commonly been used to examine the relation between dose/plasma concentration and occupancy to predict relevant dose intervals in a clinical setting. In this study 11 control subjects were examined with PET and [¹¹C]MADAM at baseline, after a single dose and after 9 days of dosing with Lu AA21004 (2.5, 10 or 60 mg) for quantification of 5-HTT occupancy. Four subjects were examined with PET and [¹¹C]WAY 100635 at baseline, after a single dose and after 9 days of dosing of Lu AA21004 (30 mg) for quantification of 5-HT(1A) occupancy. To allow for quantification of binding in the raphe nuclei, PET data were analyzed using wavelet aided parametric imaging. 5-HTT occupancy ranged from 2 (mean, 2.5 mg day 1) to 97% (60 mg day 9). The apparent affinity of Lu AA21004 binding to 5-HTT (KD(ND)) was calculated to 16.7 nM (R=0.95), and the corresponding oral dose (KD(ND)-dose) to 8.5 mg (R=0.91). No significant occupancy of 5-HT(1A) receptors was found after dosing of 30 mg Lu AA21004. Based on the literature and the present [¹¹C]MADAM binding data, a dose of 20-30 mg Lu AA21004 is suggested to give clinically relevant occupancy of the 5-HTT.
Keywords:
5-HT(1A) receptor; 5-HTT; Lu AA21004; Occupancy; PET.
Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.
Publication types
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Benzylamines / metabolism
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Benzylamines / pharmacokinetics
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Carbon Radioisotopes
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Dose-Response Relationship, Drug
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Humans
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Ligands
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Magnetic Resonance Imaging
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Male
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Middle Aged
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Nerve Tissue Proteins / agonists
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / metabolism*
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Neurons / diagnostic imaging
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Neurons / drug effects
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Neurons / metabolism*
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Piperazines / administration & dosage
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Piperazines / metabolism
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Piperazines / pharmacokinetics*
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Piperazines / pharmacology
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Positron-Emission Tomography
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Pyridines / metabolism
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Pyridines / pharmacokinetics
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Radiopharmaceuticals / metabolism
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Radiopharmaceuticals / pharmacokinetics
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Raphe Nuclei / diagnostic imaging
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Raphe Nuclei / drug effects
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Raphe Nuclei / metabolism*
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Receptor, Serotonin, 5-HT1A / chemistry
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Receptor, Serotonin, 5-HT1A / metabolism*
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Selective Serotonin Reuptake Inhibitors / administration & dosage
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Selective Serotonin Reuptake Inhibitors / metabolism
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Selective Serotonin Reuptake Inhibitors / pharmacokinetics
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Selective Serotonin Reuptake Inhibitors / pharmacology
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Serotonin 5-HT1 Receptor Agonists / administration & dosage
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Serotonin 5-HT1 Receptor Agonists / metabolism
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Serotonin 5-HT1 Receptor Agonists / pharmacokinetics*
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Serotonin 5-HT1 Receptor Agonists / pharmacology
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Serotonin Plasma Membrane Transport Proteins / agonists
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Serotonin Plasma Membrane Transport Proteins / chemistry
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Serotonin Plasma Membrane Transport Proteins / metabolism*
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Sulfides / administration & dosage
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Sulfides / metabolism
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Sulfides / pharmacokinetics*
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Sulfides / pharmacology
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Tissue Distribution
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Vortioxetine
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Young Adult
Substances
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Benzylamines
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Carbon Radioisotopes
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HTR1A protein, human
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Ligands
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N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine
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Nerve Tissue Proteins
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Piperazines
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Pyridines
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Radiopharmaceuticals
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SLC6A4 protein, human
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Serotonin 5-HT1 Receptor Agonists
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Uptake Inhibitors
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Sulfides
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Receptor, Serotonin, 5-HT1A
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Vortioxetine
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N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide