RT Journal Article
SR Electronic
T1 In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 774
OP 781
DO 10.1124/jpet.108.136390
VO 325
IS 3
A1 Shuji Maruyama
A1 Hideo Tsukada
A1 Shingo Nishiyama
A1 Takeharu Kakiuchi
A1 Dai Fukumoto
A1 Naoto Oku
A1 Shizuo Yamada
YR 2008
UL http://jpet.aspetjournals.org/content/325/3/774.abstract
AB We evaluated the effects of five clinically used antimuscarinic agents for overactive bladder (OAB) treatment on in vivo muscarinic receptor binding in rat brain by quantitative autoradiography. There was a dose-related decrease in in vivo specific (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB) binding in each brain region of rats 10 min after i.v. injection of oxybutynin, propiverine, solifenacin, and tolterodine. Rank order of the i.v. dose for 50% receptor occupancy (RO50) of antimuscarinic agents in rat brain regions was propiverine > solifenacin > tolterodine, oxybutynin. There was a good linear relationship between in vivo (pRO50 values in the rat hippocampus) and in vitro (pKi values in human M1 receptors) receptor binding activities of propiverine, solifenacin, and tolterodine. The observed RO50 value of oxybutynin was approximately five times smaller than the predicted in vitro Ki value. The dose ratios of antimuscarinic agents for the brain receptor occupancy (RO50) to the inhibition of carbachol- and volume-induced increases in intravesical pressure (ID50), which reflects in vivo selectivity for the urinary bladder over the brain, were greater for solifenacin, tolterodine, and propiverine than oxybutynin. Darifenacin displayed only a slight decrease in specific [11C](+)3-MPB binding in the rat brain regions, and it was not dose-related. In conclusion, in vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy may provide fundamental basis for managing central nervous system (CNS) side effects in antimuscarinic therapy for OAB. It is suggested that in the treatment of OAB, CNS side effects can be avoided by antimuscarinic agents with high selectivity for the urinary bladder over the brain. The American Society for Pharmacology and Experimental Therapeutics