The blood–brain barrier (BBB) forms an interface between the circulating blood and the brain, and functions as a tremendously effective barrier for the delivery of potential neurotherapeutics into the brain parenchyma. Conversely, the BBB possesses various carrier-mediated transport systems for the uptake of small molecules, such as essential nutrients and vitamins. These transporters have become an attractive target for drug/prodrug design in an attempt to ferry drug molecules across the BBB. Central nervous system (CNS) drug delivery is often limited by poor brain penetration of the potential drug candidate. As a result of its unique barrier properties, the BBB poses a huge challenge for the delivery of potential neurotherapeutics into the brain parenchyma.¹It is estimated that only 2% of small-molecule drugs and <0.1% of novel protein and peptide pharmaceuticals developed for CNS diseases reach therapeutic concentrations in the brain.^2,3Many of the pharmacologically active drugs tend to fail early in their development as these molecules lack optimal drug-like properties, such as a relatively small molecular weight (Mw <ca. 500 g/mol); adequate lipophilicity; neutral or uncharged nature; low hydrogen bonding potential; and sufficiently high unbound plasma fraction. These are all essential to achieve passive transcellular diffusion across the tightly joined capillary endothelial cells of the BBB.^2,4

Figure 1 Transport mechanisms in BBB for endogenous compounds, such as nutrients, which can also be utilized in drug and prodrug design (modified from Everts S: Brain Barricade, C&EN Online, www.cen-online.org June 4: 33–36, 2007).

In addition to being a structural diffusion barrier, the BBB constitutes an efficient functional barrier for solutes' attempts to cross the cell membrane. The high metabolic activity of brain capillary endothelial cells and the very effective efflux systems, which actively remove solutes from the brain back to blood circulation, protect the brain from potentially harmful endo- and exogenous agents, as well as making the development of effective neurotherapeutics difficult.^5,6The adequate brain supply of various essential water-soluble nutrients, such as glucose, amino acids, vitamins and nucleotides, is ensured by a number of specific carrier-mediated inward transport mechanisms expressed in the BBB.⁷The mechanisms that enable nutrients to cross the BBB are depicted in Figure 1.