CNS demyelination successfully imaged by PET tracer targeting voltage-gated potassium channels

Researchers have developed an innovative positron emission tomography (PET) tracer—[¹⁸F]3-F-4-AP—that can reliably and noninvasively measure the damage wrought on the myelin sheath by multiple sclerosis (MS), according to results of early, preclinical testing published in Scientific Reports.

As yet, no imaging modality that can directly image demyelination exists. Magnetic resonance imaging (MRI) is currently used, but MRI is not quantitative for demyelination, nor can it distinguish between demyelination and inflammation, which are often both present in patients with MS.

“All existing PET tracers used for imaging demyelination bind to myelin and, consequently, demyelinated lesions show as decreases in signal, which can be problematic for imaging small lesions,” said lead author Pedro Brugarolas, PhD, faculty member, Massachusetts General Hospital/Harvard Medical School, Boston, MA. “3-F-4-AP is the first tracer whose signal increases with demyelination, potentially solving some of the problems of its predecessors.”

This study took 6 years to complete and involved a large, multidisciplinary team of experts in animal models, neuroscience, chemistry, electrophysiology, and PET imaging. Researchers used autoradiography to demonstrate that 4-aminopyridine (dalfampridine, 4 AP), an MS treatment drug, exhibits higher binding in nonmyelinated and demyelinated regions of the central nervous system (CNS) compared with well-myelinated regions.

They then developed 3-fluoro-4-aminopyridine (3-F-4-AP), a fluorine-containing derivative of 4-AP, with similar pharmacologic properties that can be labeled with fluorine-18 (¹⁸F) for PET imaging. This radioactive molecule targets voltage-gated potassium channels. Without the protection of the myelin sheath, these channels are exposed, leak intracellular potassium, and are unable to process electrical impulses.

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

Results were successful.

“We were able to show, in rats, that the tracer accumulated to a higher degree in demyelinated areas than in control areas,” said Dr. Popko.

In collaboration with scientists from the National Institutes of Health, researchers confirmed in a study with healthy monkeys that the radiolabeled 3-F-4-AP enters the brain and localizes to areas with little myelin.

“We think that this PET approach can provide complementary information to MRI which can help us follow MS lesions over time,” said Dr. Popko. “It has the potential to track responses to remyelinating therapies, an unmet need. This approach should also help determine how much disruption of the myelin sheath contributes to other CNS disorders.”

Indeed, noted Dr. Popko, the other CNS disorders in which this approach may be valuable include leukodystrophies, traumatic brain injury, spinal cord injury, and “even maladies not traditionally associated with demyelination such as brain ischemia, psychiatric disorders, and neurodegenerative diseases, including Alzheimer’s.”

This research was supported by the National Multiple Sclerosis Society, the National Institute for Neurological Disorders and Stroke, the National Institute for Biomedical Imaging and Bioengineering, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Chicago Innovation Exchange (now known as the Polsky Center).