期刊
EUROPEAN NEUROPSYCHOPHARMACOLOGY
卷 23, 期 10, 页码 1190-1198出版社
ELSEVIER
DOI: 10.1016/j.euroneuro.2013.01.002
关键词
Lu AA21004; PET; 5-HIT; 5-HT1A receptor; Occupancy
资金
- AFA sjukforsakrings jubileumsstipendier (AFA Insurance)
- Karolinska Institutet
- Stockholm Centre for Psychiatric Research and Education
- H. Lundbeck A/S, Denmark
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 [C-11]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 [C-11]WAY 100635 at baseline, after a single dose and after 9 days of dosing of Lu AA21004 (30 mg) for quantification of 5-HT1A 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 (K-D(ND)) was calculated to 16.7 nM (R=0.95), and the corresponding oral dose (K-D(ND)-dose) to 8.5 mg (R=0.91). No significant occupancy of. 5-HT1A receptors was found after dosing of 30 mg Lu AA21004. Based on the literature and the present [C-11]MADAM binding data, a dose of 20-30 mg Lu AA21004 is suggested to give clinically relevant occupancy of the 5-HTT. (C) 2013 Elsevier B.V. and ECNP. All rights reserved.
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