The hexahydro-sila-difenidol (HHSiD, 1b) and p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD, 2b) derivatives cyclohexyl [3-(2-methylimidazol-1-yl)propyl]phenylsilanol (4b) and cyclohexyl(4-fluorophenyl)[3-(2-methylimidazol-1-yl)propyl]silanol (5b) were synthesized in three-step syntheses, starting from (3-chloropropyl)cyclohexyldimethoxysilane. In addition, the corresponding carbon analogs 4a and 5a (f Si/C replacement) were prepared in twostep syntheses, starting from 2-(3-chloropropyl)-2-phenyl-1,3-dioxolane and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane, respectively. The C/Si pairs 4a/4b and 5a/5b were studied for their affinities at recombinant human muscarinic M 1 , M 2 , M 3 , M 4 , and M 5 receptors stably expressed in CHO-K1 cells by evaluating their ability to inhibit the binding of the muscarinic antagonist [ 3 H]N-methylscopolamine. These studies revealed that compounds 4a, 4b, 5a, and 5b behave as simple competitive antagonists at M 1 -M 5 receptors. The exchange of the piperidin-1-yl group of the parent compounds HHD (1a), HHSiD (1b), p-F-HHD (2a), and p-F-HHSiD (2b) by a 2-methylimidazol-1-yl moiety resulted in a novel, potent, and M 3 -preferring antimuscarinic agent, compound 4b. The affinities of compounds 4a, 5a, and 5b for muscarinic M 1 (pK i ) 7.74-7.93), M 2 (pK i ) 7.03-7.14), M 3 (pK i ) 8.04-8.11), M 4 (pK i ) 7.63-7.94), and M 5 receptors (pK i ) 7.29-7.52) were very similar at the individual receptor subtypes and in turn very similar to those of the parent compounds 1a, 2a, and 2b. In contrast, replacement of the piperidin-1-yl substituent of 1b by a 2-methylimidazol-1-yl group (f 4b) increased the affinity for M 1 -M 5 receptors up to 8.3-fold. The muscarinic receptor affinity profile of 4b was found to be M 3 (pK i ) 8.69) > M 1 (pK i ) 8.39) g M 4 (pK i ) 8.32) > M 5 (pK i ) 8.02) > M 2 (pK i ) 7.43). Thus, compound 4b displayed a M 3 versus M 2 receptor selectivity (18.2-fold). The receptor subtype affinities of the carbon compound 5a were very similar to those of the corresponding silicon analog 5b, whereas sila-substitution of 4a (f 4b) increased the affinities for M 1 -M 5 receptors, this increase being greatest at M 3 and M 5 receptors (4-fold).