New prodrug design ideas for transporter-mediated cns drug delivery

Kalle Malmioja
University of Eastern Finland, Department of Pharmacy PL 1627, 70211 Kuopio Finland

Abstract:

PURPOSE:
Central nervous system (CNS) drug delivery is a major challenge in drug design and development because the restrictions made by the blood-brain barrier (BBB). It is not uncommon that many of the pharmacologically active drug molecules designed for CNS disorders do not readily cross the BBB. Usually this is because these molecules lack essential structural features. With the prodrug approach we can design molecules that are recognized by a specific transporter at the BBB which may result in their improved brain uptake.

METHODS:
We have synthesized various amino acid prodrug derivates and analogs of a model CNS drug with the aim of utilizing the large neutral amino acid transporter (LAT1) present at the BBB for the enhanced brain permeation. An in situ rat brain perfusion technique was used to determine the transport mechanism and the ability of the compounds to cross the BBB. The 100 % brain capillary permeability-surface area (PA) product was determined for a known LAT1 substrate [14C]-L-leucine. In competition studies the PA product of [14C]-L-leucine was determined after co-perfusion with the synthesized compounds.

RESULTS:
In competition studies the synthesized LAT1-targeted prodrug candidates were able to significantly decrease the brain uptake of [14C]-L-leucine. The PA product of [14C]-L-leucine varied from 5% to 96% after co-perfusion with the compounds indicating significant binding differences within the synthesized compound series.

CONCLUSION:
We have characterized new drug design ideas for CNS drug delivery utilizing transporter-mediated prodrug approach.