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

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 [C-11]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [H-3]MK-6884/[C-11]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. [C-11]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 [C-11]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [C-11]MK-6884. These results suggest that [C-11]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.

Automated summary

Positron emission tomography (PET) ligands serve as important biomarkers and tools for drug development. This study discovered and translated the PET tracer [C-11]MK-6884 from monkeys to patients with Alzheimer's disease (AD). The tracer showed high binding affinity and selectivity to M4 muscarinic cholinergic receptors (M4Rs) and demonstrated target engagement of M4R modulators. PET imaging of [C-11]MK-6884 in AD patients identified regional differences and potential for neuropathological changes.