Research Spotlight: New PET Tracer Can Reveal Deeper Insights into Multiple Sclerosis

Pedro Brugarolas, PhD, of the Department of Radiology at Massachusetts General Hospital, and Eric Klawiter, MD, MSc, of the Department of Neurology at Massachusetts General Hospital, are co-senior authors of a paper published in the European Journal of Nuclear Medicine and Molecular Imaging, “First evaluation in multiple sclerosis using PET tracer [18F]3F4AP demonstrates heterogeneous binding across lesions.” Amal Tiss, PhD, of the Department of Radiology at Massachusetts General Hospital, and Nara Michaelson, MD, of the Department of Neurology at Massachusetts General Hospital, are co-lead authors.

Q: How would you summarize your study for a lay audience?

MRI is the standard way clinicians and researchers visualize multiple sclerosis (MS) lesions, and this provides high resolution images without radiation. However, MRI cannot clearly show how badly the protective coating on nerves is damaged, or if the nerves themselves are still there, which helps with understanding if the brain can heal. PET can fill this gap by using radiolabeled tracers that illustrate real time biological activity.

We analyzed the use of a radiolabeled substance called [18F]3F4AP as an imaging agent in Positron Emission Tomography (PET) scanning. This substance demonstrates unique signals in the white matter of the brain in patients with multiple sclerosis (MS), indicating areas where the protective covering of nerve fibers (myelin) is damaged, even when these parts of the brain appear normal on MRI images.

In particular, this imaging agent binds more strongly within MS lesions (areas of tissue damage) compared to areas in the brain that do not appear to have lesions. Using [18F]3F4AP alongside MRI may be helpful in studying the process of repairing myelin in MS, especially for clinical trials.

Q: What knowledge gap does your study help to fill?

In this study, we tested a new PET tracer that binds to voltage gated potassium channels exposed on demyelinated axons, which are uncoated nerve fibers. This tracer has the dual benefit of showing varying degrees of demyelination, the process of damaging the protective coating, based on PET signal intensity and providing information on axonal integrity, which is required for the tracer to bind. This can help us more reliably identify damaged spots in the brains of people with MS that could respond to new therapies aimed at repairing the protective coating on nerves.

Q: What methods or approach did you use?

First, we produced the research tracer and recruited volunteers (healthy controls and patients with MS) who received the tracer and underwent 2-hour PET/CT scans. Each participant also underwent a separate MRI for comparison. During the PET scan, we collected blood samples to confirm adequate tracer levels in the bloodstream. Finally, we analyzed the PET images using computational models to quantify differences that may not be visible to the naked eye.

Q: What did you find?

To our surprise and excitement, the PET images showed clear differences between healthy controls and patients with MS, and some lesions visibly lit up on the scanner. Quantitative analysis revealed an approximately 14% higher signal in individuals with MS, suggesting that the tracer is sensitive to disease-related changes.

We observed striking variability across lesions within MS patients that was not apparent on MRI, which aligns with postmortem studies that also showed that MS lesions are not uniform. Overall, these findings support our proposal that [18F]3F4AP PET may offer new ways to explore why MS affects people so differently.

Q: What are the implications?

A better understanding of lesion differences in patients with MS could help clarify disease progression and severity. More importantly, being able to distinguish between damaged areas (demyelinated lesions) that are still active and those that have already healed or scarred could be highly valuable in monitoring treatment response, particularly in clinical trials for new therapies.

Q: What are the next steps?

Since this was a small study, we need to validate the findings in a larger cohort. In addition, it will be useful to compare PET results with advanced MRI techniques that provide more detailed information than conventional MRI. We also aim to evaluate whether this new imaging method can be translated into clinical practice and used to support clinical trials.

This process will take time, but we hope to advance MS research innovation, perhaps paving the way for future therapeutics that improve quality of life for people with MS by facilitating remyelination and reducing disease-related disability.