Prolyl oligopeptidase (POP) is a ubiquitous post-proline cleaving enzyme that is highly expressed in brain. Current knowledge about the biochemical features of POP and the pharmacological action of its specific inhibitors has indicated that POP participates in several aspects of the central nervous system (CNS), including learning, memory and mood. Furthermore, a role has been suggested for POP in pathological processes such as eating and mood disorders, hypertension and cell-cycle disturbances, in addition to its proposed connection with the neurodegenerative processes which occur in Alzheimer's, Huntington's and Parkinson's diseases. The milestones responsible for the accelerated development of POP inhibitors include the discovery that these compounds reverse memory loss in animal models of drug- or lesion-induced amnesia and the observation that the expression of POP correlates with age. Today, several POP inhibitors have already been evaluated in preclinical trials as potential drugs for the treatment of natural memory deficits that occur with aging or the pathological memory loss characteristic of Alzheimer's disease. Thus, the results that are emerging from basic research on POP function will facilitate the fine-tuning of more efficient drugs to target this protease.

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Membrane transporters have long been utilized to improve the oral, hepatic, and renal (re)absorption. In the brain, however, the transporter-mediated drug delivery has not yet been fully achieved due to the complexity of the blood−brain barrier (BBB). Because L-type amino acid transporter 1 (LAT1) is a good candidate to improve the brain delivery, we developed here four novel LAT1-utilizing prodrugs of four nonsteroidal anti-inflammatory drugs. As a result, all the prodrugs were able to cross the BBB and localize into the brain cells. The brain uptake of salicylic acid (SA) was improved five times, not only across the mouse BBB but also into the cultured mouse and human brain cells. The naproxen prodrug was also transported efficiently into the mouse brain achieving less peripheral exposure, but the brain release of naproxen from the prodrug was not improved. Contrarily, the high plasma protein binding of the flurbiprofen prodrug and the premature bioconversion of the ibuprofen prodrug in the mouse blood hindered the efficient brain delivery. Thus, the structure of the parent drug affects the successful brain delivery of the LAT1-utilizing prodrugs, and the small-sized LAT1-utilizing prodrug of SA constituted a successful model to specifically deliver its parent drug across the mouse BBB and into the cultured mouse and human brain cells.

The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP-2047 on spatial memory of young (3-monthold) and old (8-to 9-month-old) scopolamine-treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats. In addition, inositol-1,4,5-trisphosphate (IP 3 ) levels were assayed in rat cortex and hippocampus after effective 2.5-day POP inhibition. KYP-2047 (1 or 5 mg/kg 30 min. before daily testing) dose-dependently improved the escape performance (i.e. latency to find the hidden platform and swimming path length) of the young but not the old rats in the water maze. POP inhibition had no consistent effect on substance P levels in cortex, hippocampus or hypothalamus, and only a modest increase in neurotensin concentration was observed in the hypothalamus after a single dose of KYP-2047. Moreover, IP 3 concentrations remained unaffected in cortex and hippocampus after POP inhibition. In conclusion, the behavioural data support the earlier findings of the promnesic action of POP inhibitors, but the mechanism of the memory-enhancing action remains unclear.In addition to the cholinergic neurones, many neuropeptides may play a role in cognitive functions such as learning and memory. These peptides include vasopressin, neurotensin, oxytocin, substance P and bradykinin [1,2]. A common feature of the above-mentioned promnesic neuropeptides is their sensitivity to prolyl oligopeptidase (POP, EC 3.4.21.26), also known as prolyl endopeptidase [1]. POP is a member of the serine protease family that hydrolyses peptide bonds at the carboxy terminal of  -proline. The effects of POP in memory disorders are somewhat conflicting. On one hand, some findings suggest that a decrease in POP activity is characteristic of a generalized process of neurodegeneration, including Alzheimer's disease and dementia [3]. However, for example in Alzheimer's disease, the changes in POP activities depend on which brain areas are being investigated. In cerebral cortex, a reduction in POP activity has been observed, whereas in occipital cortex, the POP activity seems to increase [4]. It has been proposed but not proved that these alterations in POP activity in Alzheimer's disease and dementia account for some of the observed changes in neuropeptide levels. In Alzheimer's disease, vasopressin and substance P levels decrease in cortical areas and hippocampus [5], areas implicated in cognitive processes. Furthermore, increased levels of neuropeptides have been shown to improve cognitive function in experimental animals [6,7].These observations would seem to indicate that manipulations of POP activity and its secondary effects on neuropeptide levels could represent a potential therapeutic target for treatment of cognitive disorders. Several POP inhibitors have been studied in animals. Studies with rats have demonstrated memo...