This study was performed on the basis of recently developed prodrugs of the histamine H3-receptor agonist (R)-alpha-methylhistamine (1) to determine structure-activity relationships of azomethine prodrugs of 1, in which the primary amine functionality is bioreversibly linked to aromatic ketones. Therefore, the pro-moiety was systematically altered from alkylaryl over benzylaryl to diaryl substitution. Those compounds that emerged to be stable enough during preparation were tested for their in vitro hydrolysis rates. Apparently, bulky alkyl residues were capable of preventing previously observed intramolecular cyclization, but the obtained azomethines 12a-c were far too unstable to serve as prodrugs. However, the benzylaryl imines 12d, e were stable compounds, but 12d decomposed too rapidly under in vitro conditions. Distinctly greater stability was provided by diaryl pro-moieties, even if strongly electron-withdrawing functionalities were introduced. Selected compounds were also tested in vivo following p.o. application to mice. Particularly the trifluoromethyl substituted imine 12i proved to be highly effective as stability and rate of conversion were well-balanced, so that brain penetration of 1 was strikingly facilitated. Thus 12i, a highly potent azomethine prodrug, may serve as an important pharmacological tool and, possibly, a therapeutic agent.