LAUSR

Description [11C]MK-6884 is an M4R-specific PET tracer for quantifying target engagement in brain and providing insights into AD neuropathology. Quantifying M4R engagement Activation of the M4 muscarinic receptor (M4R) might be therapeutic in patients with Alzheimer’s disease (AD). However, the development of selective agonists is hindered by the lack of in vivo methods to measure target engagement. Now, Li et al. developed a positron emission tomography (PET) tracer called [11C]MK-6884 able to bind an allosteric site of M4R with high selectivity. Characterization of the tracer in monkeys, healthy human volunteers, and patients with AD showed selective target engagement and sensitivity to the orthosteric M4R agonist carbachol in vitro and to the acetylcholinesterase inhibitor donepezil in vivo in monkeys and healthy human volunteers. The results suggest that [11C]MK-6884 could be used to measure target engagement in clinical trials and drug development. 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.