Prolyl oligopeptidase (POP) is a cytosolic serine peptidase that hydrolyzes proline-containing peptides at the carboxy terminus of proline residues. This peptidase has gained importance as a target for the treatment of cognitive disturbances of patients with neuropsychiatric diseases. Our research addresses the identification of POP inhibitors from a small focused library of polar heterocyclic compounds arising from multicomponent reactions. Two selective POP-specific inhibitors were identified on the basis of their inhibition of dipeptidyl peptidase IV. The most active compounds were evaluated for their in vitro transport through the blood-brain barrier (BBB) using a parallel artificial membrane permeability assay. Our results show for the first time that benzimidazolium salts are new POP-inhibitory scaffolds with properties of solubility, specificity, and lipophilicity that may allow them to cross the BBB by passive diffusion. These findings constitute an excellent starting point to synthesize new POP inhibitors with enhanced properties.