The loss or damage of myelin, a cellular sheath that surrounds and insulates nerves, is the hallmark of the immune-mediated neurological disorder multiple sclerosis (MS). When segments of this protective membrane are damaged, nerve impulses can be disrupted. Symptoms range from tingling and numbness to weakness, pain and paralysis.

There is currently no reliable way to directly image demyelination. Physicians rely on magnetic resonance imaging (MRI), but despite high resolution images, MRI is not quantitative and cannot distinguish between demyelination and inflammation, which often coexist in people with MS.

In the January 12, 2017 online issue of the journal Scientific Reports, a multi-institutional team based primarily at the University of Chicago Medicine and the National Institutes of Health, describe early tests of a novel minimally-invasive way to assess myelin damage using positron emission tomography (PET).
These PET scans use a radioactive molecule designed to target voltage-gated potassium channels, a protein found on demyelinated axons. The PET images, based on the detection of this molecule, provide quantitative information about underlying biochemical processes.

"In healthy myelinated neurons, potassium channels are usually buried underneath the myelin sheath," explained study author Brian Popko, PhD, the Jack Miller Professor of Neurological Disorders and director of the center for peripheral neuropathy at the University of Chicago. "When there is loss of myelin, these channels become exposed. They migrate throughout the demyelinated segment and their levels increase."

These exposed neurons leak intracellular potassium. This leaves them unable to propagate electrical impulses, which causes some of the neurological symptoms seen in MS. "So we developed a PET tracer that can target potassium channels," Popko said.

The team started with an existing MS drug, 4-aminopyridine (a.k.a. dalfampridine), which can bind to exposed potassium channels. This can partially restore nerve conduction and alleviate neurological symptoms in MS patients. Using mouse models of MS, including some developed in the Popko lab, the researchers showed that the drug accumulated in the demyelinated, or uncovered, areas of the central nervous system.

Then, with help from colleague Pancho Bezanilla, PhD, professor of biochemistry and molecular biology at the University of Chicago, the team examined several fluorine-containing derivatives of 4-aminopyridine for binding to K+ channels. They found that 3-fluoro-4-aminopyridine (3F4AP) has the desired properties, so they labeled the molecule with fluorine-18, which is easily detected by PET.

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