PET Tracer for Myelin Loss Shows Good Safety in 1st-in-human Study

Scientists: New tracer may help evaluate demyelination in MS

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A novel tracer designed to detect myelin loss in PET scans — imaging tests that use a radioactive substance, called a tracer, to look for disease in the body — showed a good safety profile in a small first-in-human study.

Scientists say this new tracer could potentially help in evaluating multiple sclerosis (MS) and other neurological diseases characterized by demyelination, or damage to the protective covering on nerves.

An ongoing clinical trial (NCT04699747) is now testing the tracer, called [18F]3F4AP, in up to 60 healthy volunteers and MS patients. The trial is recruiting participants at Massachusetts General Hospital (MGH), in Boston.

“Giving a new tracer to humans is a big deal as it requires being able to make the tracer in a sterile environment, demonstrating to the U.S. Food and Drug Administration that the trace meets a very strict quality control and getting permission from the agency to administer it to humans,” Georges El Fakhri, PhD, director of the hospital’s Gordon Center for Medical Imaging and co-author of the study, said in an MGH press release.

“Once a tracer has been in humans for the first time and it has been shown to be safe — which is what this study shows — it is easier for other researchers to use it,” said El Fakhri, also a professor of radiology at Harvard Medical School.

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The study, “Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP,” was published in the European Journal of Nuclear Medicine and Molecular Imaging.

Myelin is a fatty sheath that wraps around nerve fibers, helping them to send electrical signals, sort of like insulation around a wire. In MS, inflammation in the brain and spinal cord damages myelin, disrupting neuronal signaling and ultimately causing disease symptoms.

Techniques for detecting demyelination

While imaging techniques like MRI can detect neuronal damage in MS, they generally cannot distinguish myelin loss (demyelination) from other forms of damage that may accrue.

The [18F]3F4AP tracer can specifically bind to proteins called Kv1.1 and Kv1.2. These two protein channels are found on the outside of nerve fibers and are normally buried under the myelin sheath. When myelin is lost, they become exposed — and given that, the tracer may be useful as a marker of myelin loss.

The tracer was created by modifying the active ingredient in Ampyra (dalfampridine), a therapy used to improve walking in MS. It is thought to work by binding to the Kv1.1 and Kv1.2 proteins to improve electrical signaling in nerve cells.

“Having an imaging tool that it is specific to demyelination can help to better understand the contribution of demyelination to different diseases and better monitor a disease or the response to therapy—for example, a remyelinating therapy,” said Pedro Brugarolas, PhD, a Harvard professor and study co-author.

Although the [18F]3F4AP tracer had shown promise at detecting myelin loss in animal models, it had never before been given to humans.

In this preliminary study (NCT04710550), the tracer was administered to four healthy adult volunteers — two women and two men — between the ages of 20 and 59. All participants received a single dose of the tracer, given into the bloodstream, then underwent PET imaging and safety assessments.

Safety assessments were generally unremarkable, with no noteworthy changes in vital signs or other adverse outcomes reported. The tracer’s movement through the participants’ bodies was generally in line with expectations from earlier animal experiments, though the tracer was cleared from the body somewhat more quickly in humans.

Specifically, less than 50% of the initial compound remained in circulation in the human participants one hour after injection, compared with 90% after three hours in monkeys.

It also was cleared faster than Ampyra — more than 70% of that therapy remains in circulation 24 hours after administration — which the researchers said is “worth investigating further.”

“Although this study only included a small number of volunteers, the tracer and study procedures were well tolerated among study participants as it is expected for PET tracers,” the researchers concluded.

“In addition, this study showed that the radiation dose in humans is within the acceptable levels, and that the tracer readily enters the brain opening the door for additional studies investigating the ability of [18F]3F4AP to detect demyelinated lesions in different patient populations,” they added.

According to the researchers, this tracer has the potential to help advance the diagnosis and treatment of MS and other disorders.

“A tracer that allows quantitative imaging of demyelination in humans may contribute to better understanding of the [disease] processes, more accurate diagnoses of brain diseases, and provide a tool for accurately monitoring remyelinating therapies,” they wrote.

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