MK-6884 is a M4 Muscarinic Receptor PAM for Neurodegenerative Disease Research

mAChRs (muscarinic acetylcholine receptors) are G-protein-coupled receptors and exist in five subtypes. The M1, M3 and M5 receptors are excitatory receptors. Meanwhile, M2 and M4 receptors inhibit neuronal firing by decreasing the intracellular concentration of cAMP and activating G-protein coupled inward rectifying potassium channels. The five mAChRs play important in numerous diseases, including neurodegenerative and psychiatric disorders. In particular, the M1 and M4 mAChRs have been associated with neurological illnesses. Because they widely exist in the central nervous system. And they play an important role in cognitive processes such as attention, learning, and memory.

The M4 mAChR participates in the regulation of dopamine levels in the brain. Activation of M4 receptors inhibits acetylcholine release in the striatum. Indeed, M4 mAChRs and D1 dopamine receptors are coexpressed throughout the striatum. Activation of M4 receptors in the striatum inhibit D1-induced locomotor stimulation in mice. Research shows lower levels of M4 mAChRs in postmortem brain tissues of schizophrenic patients. Modulators that selectively target M4 mAChR could thus be useful in the research of diseases such as Alzheimer’s disease and schizophrenia.

MK-6884 is a M4 muscarinic receptor positive allosteric modulator (PAM). Therefore, MK-6884 has potential for neurodegenerative disease research. [11C]MK-6884 is a positron emission tomography (PET) tracer for in vivo imaging of the M4 allosteric binding site in brain. Noninvasive imaging of M4 PAMs using PET allows quantification of the distribution, expression, and modulation of this receptor under physiological and pathological conditions. [11C]MK-688 can penetrate the blood-brain barrier in monkeys. Therefore, [11C]MK-6884 distributes on the known presence of M4 receptors in the rhesus monkeys brain after a single intravenous injection.

[1]. Leach K, et, al. Neuropsychopharmacology. 2010 Mar;35(4):855-69.