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Regional brain mGlu5 receptor occupancy following single oral doses of mavoglurant as measured by [11C]-ABP688 PET imaging in healthy volunteers

Authors :
Johannes Streffer
Valerie Treyer
Alfred Buck
Simon M. Ametamey
Milen Blagoev
Ralph P Maguire
Aurélie Gautier
Yves P. Auberson
Mark E. Schmidt
Ivan-Toma Vranesic
Baltazar Gomez-Mancilla
Fabrizio Gasparini
Source :
NeuroImage, Vol 230, Iss , Pp 117785- (2021)
Publication Year :
2021
Publisher :
Elsevier, 2021.

Abstract

Mavoglurant binds to same allosteric site on metabotropic glutamate receptor 5 (mGluR5) as [11C]-ABP688, a radioligand. This open-label, single-center pilot study estimates extent of occupancy of mGluR5 receptors following single oral doses of mavoglurant, using [11C]-ABP688 positron emission tomography (PET) imaging, in six healthy males aged 20–40 years. This study comprised three periods and six subjects were divided into two cohorts. On Day 1 (Period 1), baseline clinical data and safety samples were obtained along with PET scan. During Period 2 (1–7 days after Period 1), cohort 1 and 2 received mavoglurant 25 mg and 100 mg, respectively. During Period 3 (7 days after Period 2), cohort 1 and 2 received mavoglurant 200 mg and 400 mg, respectively. Mavoglurant showed the highest distribution volumes in the cingulate region with lower uptake in cerebellum and white matter, possibly because myelinated axonal sheets maybe devoid of mGlu5 receptors. Maximum concentrations of mavoglurant were observed around 2–3.25 h post-dose. Mavoglurant passed the blood–brain barrier and induced dose- and exposure-dependent displacement of [11C]-ABP688 from the mGluR5 receptors, 3–4 h post-administration (27%, 59%, 74%, 85% receptor occupancy for mavoglurant 25 mg, 100 mg, 200 mg, 400 mg dose, respectively). There were no severe adverse effects or clinically significant changes in safety parameters.This is the first human receptor occupancy study completed with Mavoglurant. It served to guide the dosing of mavoglurant in the past and currently ongoing clinical studies. Furthermore, it confirms the utility of [11C]-ABP688 as a unique tool to study drug-induced occupancy of mGlu5 receptors in the living human brain.

Details

Language :
English
ISSN :
10959572
Volume :
230
Issue :
117785-
Database :
Directory of Open Access Journals
Journal :
NeuroImage
Publication Type :
Academic Journal
Accession number :
edsdoj.72d8efd5c49d88ff715c43ad5a8a3
Document Type :
article
Full Text :
https://doi.org/10.1016/j.neuroimage.2021.117785