title: Effect of oxybutynin and imidafenacin on central muscarinic receptor occupancy and cognitive function: a monkey PET study with [(11)C](+)3-MPB.
abstract: 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-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB). The scan sequence was pre, and 1, 4, and 24h post oral administration of oxybutynin (0.1-1.0mg/kg) or imidafenacin (0.01-0.1mg/kg). Maximum cognitive impairment was observed 1h post-oxybutynin at oral doses of 0.3 and 1.0mg/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.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Stockholm, Sweden.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Shuji
authors.initials: S
authors.lastname: Maruyama
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kawamata
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishiyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohba
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
mesh_terms: D000465:Algorithms; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005556:Form Perception / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D008239:Lysine / Q000031:analogs & derivatives*; D008253:Macaca mulatta; D008297:Male; D008301:Maleimides; D008333:Mandelic Acids / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010775:Photic Stimulation; D049268:Positron-Emission Tomography; D011597:Psychomotor Performance / Q000502:physiology; D019275:Radiopharmaceuticals; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D008301:Maleimides; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D019275:Radiopharmaceuticals; D011976:Receptors, Muscarinic; C047272:3-(N-maleimidopropionyl)biocytin; D008239:Lysine; C005419:oxybutynin; C120953:imidafenacin