Effect of oxybutynin and imidafenacin on central muscarinic receptor occupancy and cognitive function: A monkey PET study with [11C](+)3-MPB

Although antimuscarinic agents are widely used to treat overactive bladder (OAB), they have been shown to induce side effects including dry mouth and cognitive impairment. The present study was aimed to investigate the effects of antimuscarinic agents, oxybutynin and imidafenacin, on temporal changes in cognitive function and central mAChR occupancy in conscious monkeys (Macaca mulatta). Three conscious monkeys underwent positron emission tomography (PET) scans with a mAChR radioligand N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB). The scan sequence was pre, and 1, 4, and 24 h post oral administration of oxybutynin (0.1–1.0 mg/kg) or imidafenacin (0.01–0.1 mg/kg). Maximum cognitive impairment was observed 1 h post-oxybutynin at oral doses of 0.3 and 1.0 mg/kg, in a dose-dependent manner, and oxybutynin produced significant positive correlations between mAChR occupancy and cognitive impairment in the cortices, thalamus, brainstem, and striatum. The most significant correlation was observed in the brainstem, and then cortices. In contrast, imidafenacin did not induce discernible cognitive impairment, despite having obtained some lesser occupancy in cortices and brainstem. We propose that the thresholds of mAChR occupancy to produce cognitive impairment by antimuscarinic agents are ca. 30–40% in cortices and ca. 20–30% in brainstem, and a desirable drug for OAB treatment should not occupy central mAChR above these thresholds.

Research highlights
► Clinical doses of oxybutynin but not imidafenacin impaired cognition in monkeys.
► Muscarinic receptor occupancy in brain was measured by positron emission tomography.
► Occupancy thresholds to impair cognition are 30–40% (cortex) and 20–30% (brainstem).