Even the most promising drug will fail if it never reaches its target. So before starting large clinical trials, pharmaceutical companies must determine, among other things, the precise dosage to use, a process that can be expensive and time-consuming. Scientists investigating a drug for Parkinson's disease have now shown how an MRI scan can quickly determine the optimal dosage for drugs that act on the brain.
Seeing red: Arterial spin labeling shows increased blood flow to key areas of the brain after patients took a new Parkinson's drug. Red indicates the areas that saw the biggest increase across many different patients.
The most precise way to track drugs as they move through the body is a PET (positron emission tomography) scan, in which a drug is a radioactively tagged, injected into the body, and tracked with a scanner. But PET scans have several drawbacks, notes Kevin Black, associate professor of psychiatry at Washington University in St. Louis, Missouri, who led the new research, published in the December issue of The Journal of Neuroscience. PET scanners, and PET scans, are very costly. And because they expose subjects to radioactivity, multiple PET scans can pose a health risk. As an alternative to PET scans, drug companies sometimes spend months to years assessing optimal dosages via clinical measures such as mood questionnaires or tests of patients' manual dexterity.
The Washington University study, funded by Synosia Therapeutics, is the first to track a drug's effect with an MRI technique called arterial spin labeling (ASL). Using this approach, the researchers determined the optimal dosage of the Parkinson's drug noninvasively, without injections or radioactivity, in four months.
The researchers focused the MRI machine on subjects' neck arteries to tag water molecules in the blood by changing their magnetic properties. These water molecules were visible in subsequent scans, providing a picture of arterial blood flow to particular parts of the brain.
The researchers took scans before and after the administration of different doses of the drug. When they compared the shots, Black and colleagues could see immediately which areas of the brain implicated in Parkinson's showed increased blood flow, owing to the action of the drug. This allowed them to identify the most effective dosage for further testing.
Using ASL to accelerate the move to large trials will interest drug companies as a cost-cutting measure, says the University of Pennsylvania's John Detre, a neurologist who developed ASL in the early 1990s and was not involved in the new research. "A key go/no-go decision in drug development early on is whether the drug is getting into the brain and doing what you think it's doing," he says. "This study is a fantastic proof of principle."
ASL doesn't have the specificity of PET scans, which can track the way drugs act at a molecular level, says Luis Hernandez of the University of Michigan's MRI Research Facility. "But if you want to know if the drug is changing the part of the brain it should be reaching," he remarks, "then this works well."
An obvious target for ASL is antidepressants, which take two to six weeks or longer to show a clinical effect. With ASL, it is possible to see very quickly whether the drug is affecting the brain—an indication that it could be effective in alleviating depression. Detre adds that the technique could see more use in other areas of drug development: "You might be able to use this one technique to look at the effects of a very broad range of drugs on the brain."
By Veronique Greenwood
From Technology Review