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

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Valerie Treyer¹  Alfred Buck¹  Milen Blagoev¹  Johannes Streffer²  Aurélie Gautier³  Fabrizio Gasparini⁴  Yves P. Auberson⁴  Ralph P Maguire⁴  Mark E. Schmidt⁴  Ivan-Toma Vranesic⁴  Baltazar Gomez-Mancilla⁴  Simon M. Ametamey⁵ 

[1] Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland;Division of Psychiatric Research, University of Zurich, Zurich, Switzerland;Global Drug Development, Novartis Pharma AG, Basel, Switzerland;Novartis Institutes for Biomedical Research, Novartis Pharma AG, Postfach, Basel CH-4002, Switzerland;Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Zurich, Switzerland;

关键词: Mavoglurant;    mGluR5;    PET imaging;    Receptor occupancy;    Single oral dose;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown