Chapter 28 - Blood-Brain Barrier Methods

Abstract

Brain penetration is a major barrier for some compound series. Brain penetration is limited by blood–brain barrier (BBB) permeation and brain distribution. Each of these is determined by multiple underlying mechanisms. Understanding the difference between BBB permeation and brain distribution can lead to more effective data interpretation and successful planning for structure modification to enhanced brain penetration. Most companies performing neuroscience drug discovery research use a combination of methods to better determine the brain penetration characteristics of their leads. A combination of data from in vivo and in vitro methods can reveal and confirm predominant BBB mechanisms for a compound. Commercial software for predicting BBB penetration is available. Cell-based BBB assays have inherent appeal as in vitro models of BBB permeation because they are living and, presumably, closer to the BBB than physicochemical methods. Endothelial cell cultures have been used for detailed BBB studies but are not common for moderate- to high-throughput applications. Several methods are available for assessing brain penetration. This provides discovery scientists with insights into whether their project compounds are expected to have any problems with penetrating to the therapeutic target in the brain. Results provide more in-depth assessment of penetration into the brain as well as feedback (validation) on whether the early assessment of passive brain penetration was correct.