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.”
Although antibodies are now considered mainstream therapeutics, their potential for imaging agents as intact molecules is limited. They lack suitable pharmacokinetics and distribution within the body. This is the rationale behind the research of Anna Wu, Ph.D., professor of molecular and medical pharmacology at UCLA Medical School. “We want to capture the specificity of antibodies, but for imaging purposes.”
Her group has developed antibody fragments in three different formats to provide a variety of different pharmacokinetic and clearance patterns. The fragments are based on single-gene variable fragments, and re-formatting works the majority of the time. However, occasionally there is a loss of activity or affinity and this requires additional work to restore the desired binding.
Most applications being pursued are in cancer (solid tumors), using antibodies directed against cancer cell surface targets. “This approach allows us to control both the pharmacokinetics (Pk) and the primary organ of clearance. The Pk is important because we want to match that to the half-life of the selected isotope we’re using for imaging,” stated Dr. Wu.
The fragments include diabodies (55K molecular weight), minibodies (80K molecular weight), and single-chain Fv-FC (105 to 110K). The diabodies clear the body most quickly, followed by the larger fragments. This provides more control over where the fragments clear—diabodies clear via the kidneys and the larger fragments via the liver.
All fragments can be labeled with radionuclides for SPECT or PET. Dr. Wu’s group is focused more on PET because it is more sensitive and quantitative and is also a mainstay for oncology due to the availability and use of Fluorine-18 labeled FDG (fluorodeoxyglucose)—a glucose analog.
In the academic setting, Dr. Wu says they have developed about 6 to 12 fragments that have been used in preclinical mouse cancer models. In addition, Dr. Wu says that her group and others have published a few early studies evaluating engineered antibodies in the clinic. Commercially, she co-founded ImaginAb in 2007 to further develop these engineered fragments as clinical imaging agents.
ImaginAb has identified three disease areas with unmet clinical imaging needs and has in-licensed antibodies to develop imaging agents. “We’re partnering with pharma companies because these imaging agents can be useful along the drug development path—for example, helping to select patients for clinical studies and monitoring treatment response. Another one of our goals is to provide these companies with companion imaging biomarkers.”