Transporter-Mediated Brain-Targeted Prodrugs

3/12/2019 16:15 - 16:50

Diseases of the central nervous system (CNS) are one the greatest threats to public health and the direct and indirect healthcare costs of these are expected to increase as the population ages. However, most brain disorders and diseases lack effective drug therapies. The blood-brain barrier (BBB) prevents the uptake of numerous drug molecules into the brain. Therefore, there is an enormous and growing unmet need to improve CNS drug delivery to provide better medicines for humankind in future.

L-Type amino acid transporter 1 (LAT1) is a sodium- and pH-independent heterodimeric transmembrane protein that carries bulky and neutral amino acids into the cells. It is highly expressed on the cell surfaces that require a constant amino acid supply, such as endothelial cells of the BBB, neurons and glial cells, and over-expressed in several cancer cell types. In addition to amino acids, LAT1 also carries drugs and therefore, it can have a major role in drugs’ brain disposition. If a drug is not a LAT1-substrate, it can be converted as a LAT1-utilizing prodrug to improve its brain uptake and intra-brain targeting.


In this presentation, several examples of LAT1-utilizing prodrugs of neuroprotective agents are presented. Their LAT1-utilization, BBB permeation, target cell selective uptake, brain-targeting efficacy and pharmacokinetics are summarized. Moreover, the bioconversion of the LAT1-utilizing prodrugs in targets cells as well their premature bioconversion due to the first pass metabolism and the species differences of bioconverting enzymes are discussed. Finally, it will be demonstrated that by converting neuroprotective drugs, such as antioxidants, anti-inflammatories and immunomodulative agents, to LAT1-utilizing brain-targeted prodrugs can yield to improved efficacy followed by selected biomarkers.