The metabotropic glutamate receptor 5 radioligand [11C]AZD9272 identifies unique binding sites in primate brain.

Abstract

The metabotropic glutamate receptor 5 (mGluR5) is a target for drug development and for imaging studies of the glutamate system in neurological and psychiatric disorders. [11C]AZD9272 is a selective mGluR5 PET radioligand that is structurally different from hitherto applied mGluR5 radioligands. In the present investigation we compared the binding patterns of radiolabeled AZD9272 and other mGluR5 radioligands in the non-human primate (NHP) brain. PET studies were undertaken using [11C]AZD9272 and the commonly applied mGluR5 radioligand [11C]ABP688. Autoradiography studies were performed in vitro using [3H]AZD9272 and the standard mGluR5 radioligands [3H]M-MTEP and [3H]ABP688 in NHP tissue. Competition binding studies were undertaken in vivo and in vitro using different mGluR5 selective compounds as inhibitors. In comparison to other mGluR5 radioligands radiolabeled AZD9272 displayed a distinct regional distribution pattern with high binding in ventral striatum, midbrain, thalamus and cerebellum. While the binding of [11C]AZD9272 was almost completely inhibited by the structurally unique mGluR5 compound fenobam (2.0 mg/kg; 98% occupancy), it was only partially inhibited (46% and 20%, respectively) by the mGluR5 selective compounds ABP688 and MTEP, at a dose (2.0 mg/kg) expected to saturate the mGluR5. Autoradiography studies using [3H]AZD9272 confirmed a distinct pharmacologic profile characterized by preferential sensitivity to fenobam. The distinctive binding in ventral striato-pallido-thalamic circuits and shared pharmacologic profile with the pro-psychotic compound fenobam warrants further examination of [11C]AZD9272 for potential application in psychiatric neuroimaging studies.

• Authors: Katarina Varnäs, Anders Juréus, Sjoerd J Finnema, Peter Johnström, Patrick Raboisson, Nahid Amini, Akihiro Takano, Vladimir Stepanov, Christer Halldin, Lars Farde
• Journal: Neuropharmacology (Neuropharmacology) Vol. 135 Pg. 455-463 (06 2018) ISSN: 1873-7064 [Electronic] England
• PMID: 29608920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• AZD9272
• Imidazoles
• Oxadiazoles
• Pyridines
• Radiopharmaceuticals
• Receptor, Metabotropic Glutamate 5
• fenobam

Topics

• Allosteric Regulation
• Animals
• Autoradiography
• Binding Sites
• Binding, Competitive
• Brain (diagnostic imaging, metabolism)
• Female
• Imidazoles (pharmacology)
• Macaca fascicularis
• Male
• Oxadiazoles (pharmacokinetics)
• Positron-Emission Tomography
• Pyridines (pharmacokinetics)
• Radiopharmaceuticals (pharmacokinetics)
• Receptor, Metabotropic Glutamate 5 (antagonists & inhibitors, metabolism)