Drug Action in the Brain
Researchers at Brookhaven National Laboratory are developing tracer molecules for imaging drugs in the brain. This has unique challenges, says Joanna Fowler, Ph.D., senior chemist, and director of the radiotracer chemistry, instrumentation and biological imaging program.
“Designing these molecules is one of the biggest challenges because we can’t accurately predict how a molecule is going to behave in a living system.” Another challenge is developing synthetic methods that work efficiently and rapidly for incorporating short-lived isotopes into these molecules. A third challenge is designing a drug molecule with a part that can be labeled in case there’s a need to know where the drug goes and where it binds.
“If you are developing a drug for binding to some glutamate transporter for depression, for example, think of putting a structural feature in the small molecule so you can eventually label it, like carbon-11 or fluorine. If you think this way when you are just developing a drug, there are many molecules that can be labeled.”
Dr. Fowler’s group has developed new methods to incorporate C-11 into organic compounds, increasing the potential number of structures available for labeling.
Her group has also worked with drug companies that want to know how much of a drug to administer in clinical trials. If the company has a drug that binds to dopamine receptors, and her group has a tracer for these receptors, it provides information on the occupancy of the receptors and how much drug to give and how often. Once a drug passes safety guidelines, the tracers, used with PET, can provide efficacy information. “You can measure concentrations of the drug in plasma and see if it correlates with what engages the target in the brain—if it does, you would have a biomarker.”
A growing area of research is focused on epigenetics. “We’re very interested in the enzymes that put epigenetic marks on DNA. There are enzymes that put methyl groups on DNA and shut down gene expression that are sometimes heritable. It’s one way of explaining how environment impacts disease and behavior.”
Dr. Fowler’s group is learning more and more that environmental factors, especially in childhood, can dramatically influence phenotypes (behavior and disease). “We’re interested in enzymes that modify chromatin and cause changes in the brain. Drugs of abuse can have a profound effect on chromatin and gene expression. We’d like to be able to image these changes. So many problems start with the brain—behavior, addiction, violence, for example. If we can understand the molecular basis of that and develop treatment, it would make a huge difference.”