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NEUROPHARMACOLOGY

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Department of Pharmacokinetics and Pharmacodynamics, Medical Biochemistry and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (S.M., N.O., S.Y.); and Central Research Laboratory, Hamamatsu Photonics, Hamamatsu, Shizuoka, Japan (H.T., S.N., T.K., D.F.)

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 (pK_i 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 K_i 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.