5-HTT and 5-HT(1A) receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects

Eur Neuropsychopharmacol. 2013 Oct;23(10):1190-8. doi: 10.1016/j.euroneuro.2013.01.002. Epub 2013 Feb 18.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Benzylamines / metabolism
  • Benzylamines / pharmacokinetics
  • Carbon Radioisotopes
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism*
  • Neurons / diagnostic imaging
  • Neurons / drug effects
  • Neurons / metabolism*
  • Piperazines / administration & dosage
  • Piperazines / metabolism
  • Piperazines / pharmacokinetics*
  • Piperazines / pharmacology
  • Positron-Emission Tomography
  • Pyridines / metabolism
  • Pyridines / pharmacokinetics
  • Radiopharmaceuticals / metabolism
  • Radiopharmaceuticals / pharmacokinetics
  • Raphe Nuclei / diagnostic imaging
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / metabolism*
  • Receptor, Serotonin, 5-HT1A / chemistry
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / administration & dosage
  • Serotonin 5-HT1 Receptor Agonists / metabolism
  • Serotonin 5-HT1 Receptor Agonists / pharmacokinetics*
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / agonists
  • Serotonin Plasma Membrane Transport Proteins / chemistry
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / metabolism
  • Serotonin Uptake Inhibitors / pharmacokinetics
  • Serotonin Uptake Inhibitors / pharmacology
  • Sulfides / administration & dosage
  • Sulfides / metabolism
  • Sulfides / pharmacokinetics*
  • Sulfides / pharmacology
  • Tissue Distribution
  • Vortioxetine
  • Young Adult

Substances

  • Benzylamines
  • Carbon Radioisotopes
  • HTR1A protein, human
  • Ligands
  • N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine
  • Nerve Tissue Proteins
  • Piperazines
  • Pyridines
  • Radiopharmaceuticals
  • SLC6A4 protein, human
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Sulfides
  • Receptor, Serotonin, 5-HT1A
  • Vortioxetine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide