Image-Guided Drug Design

To treat brain disorders such as schizophrenia, not only do drugs need to be potent, but they also need to slip past the defenses of the blood-brain barrier to reach their targets. Looking for ways to fill this tall order, a research team led by Jacob M. Hooker of Harvard Medical School and Sung Won Kim of NIH’s National Institute on Alcohol Abuse & Alcoholism has developed a drug design strategy that combines brain imaging and lab assays (ACS Chem. Neurosci. 2014, DOI: 10.1021/cn500021p). The scientists began with a promising anticancer compound, MS-275, that blocks the enzyme histone deacetylase (HDAC). “It had been reported that it was a long-lasting inhibitor that gets into the brain,” Hooker tells C&EN. But when the team placed a radiolabel on the molecule and used positron emission tomography (PET) to image its uptake in the brains of baboons, they were disappointed. Undeterred, the researchers modified the compound, ran a few new versions of it through an assay to check for HDAC activity, and ran the PET scans again. After a few more rounds, the researchers hit upon a series of HDAC inhibitors capable of penetrating the brain. According to Hooker, the strategy offers a way “to optimize a series of candidates for brain penetration.”