title: 5-HTT and 5-HT(1A) receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects.
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.
authors: Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital Solna, Building R5, 171 76 Stockholm, Sweden.
authors: Per
authors: P
authors: Stenkrona
authors: Christer
authors: C
authors: Halldin
authors: Johan
authors: J
authors: Lundberg
mesh_terms: D000328:Adult; D001596:Benzylamines / Q000378:metabolism / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics; D011903:Raphe Nuclei / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013440:Sulfides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution; D000078784:Vortioxetine; D055815:Young Adult
chemical_list: D001596:Benzylamines; D002250:Carbon Radioisotopes; D008024:Ligands; D009419:Nerve Tissue Proteins; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D044282:Receptor, Serotonin, 5-HT1A; D058825:Serotonin 5-HT1 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; D000078784:Vortioxetine; C583518:HTR1A protein, human; C470437:N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine; C493230:SLC6A4 protein, human; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
keywords: 5-HT(1A) receptor; 5-HTT; Lu AA21004; Occupancy; PET