ISBN : 978-93-85073-24-3 Fig 1.2: Whole body autoradiogram of an adult mouse sacrificed 30 min after intravenous injection of radiolabeled histamine, a small molecule that readily enters all organs of the body, except for the brain and spinal cord. The transport of small molecules across the BBB is the exception rather than the rule, and 98% of all small molecules do not cross the BBB [117]. Despite the large number of patients with disorders of the CNS and despite the fact that so few large or small molecule therapeutics cross the BBB, there are few pharmaceutical companies in the world today that have built a BBB drug targeting program. However, even if a pharmaceutical company decided to develop a BBB program, there would be few BBB-trained scientists to hire because less than 1% of U. S. academic neuroscience programs emphasize BBB transport biology. Because most drugs do not cross the BBB, and because the industry is not providing solutions to the BBB problem, it is not surprising that most disorders of the CNS could benefit from improved drug therapy (Fig 1.3). For a small molecule drug to cross the BBB in pharmacologically significant amounts, the molecule must have the dual molecular characteristics of a) molecular mass under a 400- to 500-Da threshold, and b) high lipid solubility. 8
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