Streffer, Johannes, Treyer, Valerie, Buck, Alfred, Ametamey, Simon, Blagoev, Milen, Schmidt, Mark, Gautier, Aurelie, Maguire, Paul, Auberson, Yves, Vranesic, Ivan-Toma, Gomez-Mancilla, Baltazar and Gasparini, Fabrizio (2021) Regional brain mGluR5 receptor occupancy following single oral doses of mavoglurant as measured by [11C]-ABP688 PET imaging in healthy volunteers. NeuroImage, 230. ISSN 10538119

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 mGluR5 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 study can assist in defining a relevant clinical dose range for use in clinical trials, and shows that PET and [11C]-ABP688 provide a unique tool to study drug-induced occupancy of mGlu5 receptors in the living human brain.

Item Type:	Article
Date Deposited:	27 Apr 2021 00:45
Last Modified:	27 Apr 2021 00:45
URI:	https://oak.novartis.com/id/eprint/42746