Muscarinic Receptor Binding of the Novel Radioligand, [3H]Imidafenacin in the Human Bladder and Parotid Gland

• Published in: Journal of Pharmacological Sciences Vol. 124; no. 1; pp. 40 - 46
• Main Authors: Yoshida, Akira, Kuraoka, Shiori, Ito, Yoshihiko, Okura, Takashi, Deguchi, Yoshiharu, Otsuka, Atsushi, Ozono, Seiichiro, Takeda, Masayuki, Masuyama, Keisuke, Araki, Isao, Yamada, Shizuo
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 01.01.2014; The Japanese Pharmacological Society; Elsevier
• Subjects: [3H]imidafenacin; Aged; Aged, 80 and over; Binding Sites; Dose-Response Relationship, Drug; Female; human bladder; Humans; Imidazoles - metabolism; Imidazoles - therapeutic use; Male; Middle Aged; muscarinic receptor; overactive bladder; parotid gland; Parotid Gland - metabolism; Radioligand Assay; Receptor, Muscarinic M3 - metabolism; Staining and Labeling; Tritium; Urinary Bladder - metabolism; Urinary Bladder, Overactive - drug therapy; human bladder; parotid gland; [3H]imidafenacin; overactive bladder; muscarinic receptor
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.13193FP

The aim of the current study was to demonstrate highly specific and direct binding activity of tritium ([3H])-labeled imidafenacin for labeling muscarinic receptors in human bladder and parotid gland. Specific binding of [3H]imidafenacin in human tissues was saturable, reversible, and of high affinity. The Kd value for specific [3H]imidafenacin binding in the human bladder was approximately 3 times higher than that in the parotid gland. Unlabeled imidafenacin as well as the clinically used antimuscarinic agents, oxybutynin, tolterodine, and solifenacin, competed with [3H]imidafenacin for binding sites in the human bladder and parotid gland in a concentration-dependent manner, which indicated pharmacological specificity of [3H]imidafenacin binding sites. The Ki for imidafenacin in the human bladder approximately corresponded to pharmacological potency for the competitive blockade of carbachol-induced contractions of bladder, indicating a close correlation between binding affinity of imidafenacin to bladder muscarinic receptors and its pharmacological effects in the bladder. In conclusion, the current study is the first to provide direct evidence to demonstrate that imidafenacin bound muscarinic receptors in the human bladder, supporting its clinical relevance as a therapeutic agent for overactive bladder. [3H]Imidafenacin may also be a useful radioligand for labeling the M3 subtype of muscarinic receptors with higher selectivity than other radioligands.