毒蕈碱乙酰胆碱受体
纹状体
壳核
受体
毒蕈碱乙酰胆碱受体M2
化学
变构调节
尾状核
毒蕈碱乙酰胆碱受体M1
变构调节剂
结合势
神经科学
内科学
核医学
内分泌学
生物
医学
生物化学
多巴胺
作者
Vasily Belov,Nicolas J. Guehl,Sridhar Duvvuri,Philip Iredale,Sung‐Hyun Moon,Maëva Dhaynaut,Srinivas Chakilam,Alexander C MacDonagh,Peter A. Rice,Daniel Yokell,John J. Renger,Georges El Fakhri,Marc D. Normandin
标识
DOI:10.1177/0271678x241238820
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI