PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [11C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator

• Published in: Journal of cerebral blood flow and metabolism Vol. 44; no. 8; pp. 1329 - 1342
• Main Authors: Belov, Vasily, Guehl, Nicolas J, Duvvuri, Sridhar, Iredale, Philip, Moon, Sung-Hyun, Dhaynaut, Maeva, Chakilam, Srinivas, MacDonagh, Alexander C, Rice, Peter A, Yokell, Daniel L, Renger, John J, El Fakhri, Georges, Normandin, Marc D
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.08.2024
• Subjects: Allosteric Regulation; Animals; Azabicyclo Compounds - pharmacokinetics; Azabicyclo Compounds - pharmacology; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Carbon Radioisotopes; Cyclic S-Oxides - pharmacology; Female; Kinetics; Macaca mulatta; Male; Positron-Emission Tomography - methods; Radiopharmaceuticals - pharmacokinetics; Receptor, Muscarinic M4 - metabolism; M4 mAChR; emraclidine; PAM; [11C]MK-6884; neuroimaging
• DOI: 10.1177/0271678X241238820
• ISSN: 0271-678X

Stimulation of the M4 muscarinic acetylcholine receptor reduces striatal hyperdopaminergia, suggesting its potential as a therapeutic target for schizophrenia. Emraclidine (CVL-231) is a novel, highly selective, positive allosteric modulator (PAM) of M4 muscarinic acetylcholine receptors i.e. acts as a modulator that increases the response of these receptors. First, we aimed to further characterize the positron emission tomography (PET) imaging and quantification performance of a recently developed M4 PAM radiotracer, [11C]MK-6884, in non-human primates (NHPs). Second, we applied these results to determine the receptor occupancy of CVL-231 as a function of dose. Using paired baseline-blocking PET scans, we quantified total volume of distribution, binding potential, and receptor occupancy. Both blood-based and reference region-based methods quantified M4 receptor levels across brain regions. The 2-tissue 4-parameter kinetic model best fitted regional [11C]MK-6884-time activity curves. Only the caudate nucleus and putamen displayed statistically significant [11C]MK-6884 uptake and dose-dependent blocking by CVL-231. For binding potential and receptor occupancy quantification, the simplified reference tissue model using the grey cerebellum as a reference region was employed. CVL-231 demonstrated dose-dependent M4 receptor occupancy in the striatum of the NHP brain and shows promise for further development in clinical trials.