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MK-6884

目录号 : GC67979

MK-6884 是一种 M4 毒蕈碱受体正变构调节剂 (PAM),其 Ki 值为 0.19 nM。MK-6884 可用于神经退行性疾病的研究。MK-6884 可用 11C 放射标记作为正电子发射计算机断层扫描显像剂。

MK-6884 Chemical Structure

Cas No.:2102194-04-5

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10mg
¥5,400.00
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25mg
¥10,350.00
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产品描述

MK-6884 is a M4 muscarinic receptor positive allosteric modulator (PAM) with a Ki value of 0.19 nM. MK-6884 can be used for the research of the neurodegenerative diseases. MK-6884 can be conveniently radiolabeled with carbon-11 and as a positron emission tomography (PET) imaging agent[1].

MK-6884 (compound 13; 0-22 µM) is a PAM of ACh function in a cell-based Ca2+ mobilization assay, with an EC50 of 27 nM[1].

[11C]MK-6884 (compound 13) shows non-displaceable binding potential (BPND) of 0.83 in rhesus monkeys[1].
[11C]MK-6884 (approximately 185 MBq, <2 μg; single intravenous) distributes on the known presence of M4 receptors in the rhesus monkeys brain[1].
[11C]MK-688 can penetrate the blood-brain barrier in monkeys[1].

[1]. Tong L, et al. Discovery of [11C]MK-6884: A Positron Emission Tomography (PET) Imaging Agent for the Study of M4Muscarinic Receptor Positive Allosteric Modulators (PAMs) in Neurodegenerative Diseases. J Med Chem. 2020;63(5):2411-2425.

Chemical Properties

Cas No. 2102194-04-5 SDF Download SDF
分子式 C25H25N5O 分子量 411.5
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1 mM 2.4301 mL 12.1507 mL 24.3013 mL
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Research Update

The PET tracer [11C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease

Sci Transl Med 2022 Jan 12;14(627):eabg3684.PMID:35020407DOI:10.1126/scitranslmed.abg3684.

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer’s disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

Discovery of [11C]MK-6884: A Positron Emission Tomography (PET) Imaging Agent for the Study of M4Muscarinic Receptor Positive Allosteric Modulators (PAMs) in Neurodegenerative Diseases

J Med Chem 2020 Mar 12;63(5):2411-2425.PMID:32101422DOI:10.1021/acs.jmedchem.9b01406.

The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.