The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque

Rationale: The current standards of care for Alzheimer's disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of muscarinic and nicotinic receptors. The M1 muscarinic receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects.

Objectives: Here we investigated whether the selective M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow.

Results: PQCA attenuated a scopolamine-induced deficit in novel object recognition in rat, self-ordered spatial search in cynomolgus macaque, and the object retrieval detour task in rhesus macaque. Beneficial effects in each of these assays and species were observed at similar plasma drug concentrations. Furthermore, at similar drug concentrations that were effective in the behavioral studies, PQCA increased blood flow in the frontal cortex of mice, providing a translational biomarker that could be used to guide dose selection for clinical studies.

Conclusions: These findings provide a framework for appropriately testing an M1 selective compound in patients with Alzheimer's disease.