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

• Published in: NeuroImage (Orlando, Fla.) Vol. 230; p. 117785
• Main Authors: Streffer, Johannes, Treyer, Valerie, Buck, Alfred, Ametamey, Simon M., Blagoev, Milen, Maguire, Ralph P, Gautier, Aurélie, Auberson, Yves P., Schmidt, Mark E., Vranesic, Ivan-Toma, Gomez-Mancilla, Baltazar, Gasparini, Fabrizio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2021; Elsevier Limited; Elsevier
• Subjects: Allosteric properties; Anxiety disorders; Blood-brain barrier; Brain; Cerebellum; Clinical significance; Dosage; Drug dosages; Glutamic acid receptors; Glutamic acid receptors (metabotropic); Mavoglurant; mGluR5; Neuroimaging; Obsessive compulsive disorder; Parkinson's disease; PET imaging; Pharmacokinetics; Plasma; Positron emission tomography; Receptor occupancy; Single oral dose; Substantia alba; Vital signs; Single oral dose; PET imaging; mGluR5; Receptor occupancy; Mavoglurant
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2021.117785

•Mavoglurant binds to same allosteric site on mGluR5 as the radioligand [11C]-ABP688.•Mavoglurant penetrates brain and induces mGluR5 receptors occupancy in dose- and exposure-dependent manner.•Maximum concentrations of mavoglurant were observed around 2–3.25 h post-dose.•A single dose of 400 mg causes 85% receptor occupancy after 3–4 h of administration. 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.