Why are most therapeutic drugs unable to cross the blood brain barrier?
The issue of having drugs be unable to cross the blood-brain barrier is certainly significant! If you have an infection of the brain or spinal cord, for example, the drugs and routes of administration that may be used are much more limited than for infections elsewhere.
The effects of the blood-brain barrier are derived from the nature of the barrier, itself. The capillaries perfusing the central nervous system are covered by a barrier of cells and tight junctions that only allow a few specific things in: small ions and some lipid-soluble molecules. Polar molecules--even water--have specific channels that they must use to get out of the blood and into the central nervous system. These same polar molecules are also the same sorts of molecules that can be easily dissolved in the water, which is the major solvent of the blood.
You can see now that we have a big problem. If we want therapeutic agents that cross the blood-brain barrier and that also can be transported to the brain by the blood, they need to be lipid-soluble enough to cross the barrier but water-soluble enough to be dissolved in the blood! There are some molecules that are easily able to meet both criteria, namely steroids, but most other molecules are only able to fulfill one or the other requirement.