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MGH Researchers Find New Tracer Molecule That Could Help Detect Brain Injuries

Massachusetts General Hospital is a Harvard teaching hospital in Boston's West End.
Massachusetts General Hospital is a Harvard teaching hospital in Boston's West End. By Naomi S. Castellon-Perez
By Justin Lee and Lauren L. Zhang, Contributing Writers

Researchers at Harvard-affiliated Massachusetts General Hospital have found a new tracer molecule that could help detect and identify injuries in brain imaging tests, according to a Oct. 22 paper published in the Journal of Cerebral Blood Flow & Metabolism.

In many cases of brain damage or neurodegenerative diseases such as multiple sclerosis, the brain’s neurons lose their protective coating — a process called demyelination — and their potassium channels become exposed. As a result, the neurons cannot conduct neural impulses efficiently.

The novel tracer molecule, called [18F]3F4AP, can help reveal and identify injury by binding to these exposed channels, according to the MGH researchers. The tracer is “radiolabeled” so it can be seen through a technique called positron emission tomography.

Lead author Nicolas J. Guehl, an investigator in MGH’s department of radiology and a radiology instructor at Harvard Medical School, said the tracer exhibited key properties which make it suitable for brain imaging when tested in primates.

“We found that [18F]3F4AP displays favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics,” Guehl said.

Co-senior author Pedro Brugarolas, an investigator in MGH's Gordon Center for Medical Imaging and an assistant radiology professor at HMS, said the basis for [18F]3F4AP is 4-aminopyridine, a therapeutic drug used to treat multiple sclerosis. 4-aminopyridine blocks potassium channels, restoring conduction in demyelinated neurons.

“We made a few fluorine-containing derivatives of the original drug and we tested those in vitro to see which one was more potent,” Brugarolas said. “We made three or four derivatives, and then we found that [18F]3F4AP was the most promising. We’re still pursuing some of the other derivatives, but this is the one that is farthest along.”

In their research, the team took PET scans of primates while they sampled their arterial blood. Unlike other tracers or MRI scans, [18F]3F4AP showed one of the four primates had sustained a brain injury at some previous point in time.

“We were not looking for that. It was a good surprise because it showed that the tracer is very sensitive to that type of injury,” Brugarolas said.

Tonny Veenith, a consultant in neurointensive care medicine at Queen Elizabeth Hospital Birmingham, said [18F]3F4AP would provide “an amazing way to look at neuroinflammation.” Veenith said he believes [18F]3F4AP is unique in part due to its long half-life compared to common tracers.

“It would allow you to quantify new therapeutic options,” he said. “You could give the drug and sequentially image people and see if things are getting better or not.”

The United States Food and Drug Administration recently authorized an Investigational New Drug application for [18F]3F4AP. The tracer is now on track to receive approval for use in select clinical studies.

“We should be able to start doing human studies in a few weeks,” Brugarolas said.

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ResearchHarvard Medical SchoolScienceMedicine