Noninvasive evaluation of brain muscarinic receptor occupancy of oxybutynin, darifenacin and imidafenacin in rats by positron emission tomography.
OBJECTIVE
The current study was conducted to evaluate, by the noninvasive positron emission tomography (PET), the binding of antimuscarinic agents used to treat overactive bladder (OAB) to muscarinic receptors in rat brain.


METHODS
Muscarinic receptor occupancy in the rat brain after the intravenous (i.v.) injection of oxybutynin, darifenacin and imidafenacin was evaluated by using a small animal PET system, and compared with the results by ex vivo autoradiographic and ex vivo radioligand binding experiments.


RESULTS
In PET study, the i.v. injection of oxybutynin but not darifenacin or imidafenacin at pharmacological doses decreased significantly binding potential (BP) of (+)N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB) in the rat cerebral cortex and corpus striatum in a dose-dependent manner. Similarly, in the in vivo autoradiographic experiment, oxybutynin dose-dependently reduced binding of [(11)C](+)3-MPB in the brain, whereas darifenacin and imidafenacin did not. Following the i.v. injection of oxybutynin, darifenacin and imidafenacin, there was a similar degree of binding to muscarinic receptors in the bladder as demonstrated by a significant increase in apparent dissociation constant (K(d)) values for specific [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) binding. Significant binding of muscarinic receptors in the brain was observed after the injection of oxybutynin but not darifenacin or imidafenacin.


CONCLUSIONS
Oxybutynin but not darifenacin or imidafenacin has potential side effects on the central nervous system (CNS) in patients with OAB. The results reveal the noninvasive characterization of brain receptor occupancy by PET to be a powerful tool for precise evaluation of adverse CNS effects of antimuscarinic agents in pre-clinical and clinical evaluations.
Yoshida
Akira
A
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Maruyama
Shuji
S
Fukumoto
Dai
D
Tsukada
Hideo
H
Ito
Yoshihiko
Y
Yamada
Shizuo
S
D000818:Animals; D001345:Autoradiography; D001572:Benzofurans / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D008297:Male; D008333:Mandelic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011759:Pyrrolidines / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy
D001572:Benzofurans; D007093:Imidazoles; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; C101207:darifenacin; C005419:oxybutynin; C120953:imidafenacin