PET scan ‘marker’ offers new way to track ALS

A new marker substance could make it possible to trace the progression of ALS in a person’s brain using PET scans.

ALS, also known as amyotrophic lateral sclerosis or Lou Gehrig’s disease, causes progressive degeneration of the motor neurons that control muscles. People who have it suffer from muscular atrophy and paralysis, making it difficult to walk, speak, and swallow.

At best, drugs can delay the progression of the disease, but often life expectancy is only a few years after the initial diagnosis. Very little is known about the causes of the disease.

PET brain scans
PET images of sections of a mouse brain without (left) and with (right) neuroinflammation. The yellow and red areas indicate the cannabinoid receptor 2. (Credit: ETH Zurich/Simon M. Ametamey)

A new marker substance developed by ETH Zurich researchers in collaboration with specialists at St. Gallen Cantonal Hospital and University Hospital Zurich might make it possible to monitor the progression of ALS using positron emission tomography (PET). The PET imaging technique renders specific molecules on the cell surface visible within the body tissue.

The team describes the work in a paper published in the European Journal of Medicinal Chemistry.

Cannabinoid receptor

The scan uses marker substances, known as PET ligands, that adhere to these molecules via the lock-and-key principle. The radiation emitted by the radioactive markers is very short lived, with a half-life between several minutes and a few hours. This radiation is measured during the PET scan.

“The new PET ligand could help us to research ALS more effectively and to understand how the disease progresses.”

The newly developed PET ligand binds to a receptor molecule in the body’s neurotransmitter system for cannabis-based substances, known as the cannabinoid receptor 2 (CNR2). This is very common in inflamed nerve tissue, and is also found in the central nervous system of patients suffering from ALS.

“The big challenge we faced was to develop a PET ligand that only binds to CNR2, but not to the related cannabinoid receptor 1 (CNR1),” explains Simon Ametamey, a professor at the Institute of Pharmaceutical Sciences at ETH Zurich. CNR1 occurs naturally in the human brain, where it elicits the pain-relieving and intoxicating effect of cannabis.

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The researchers in Ametamey’s group synthesized a series of molecules and performed an in vitro study to measure their ability to bind to the receptors CNR2 and CNR1. The team went on to successfully test the molecule with the most obvious preference for CNR2 in rats and mice with inflamed nerve tissue.

The scientists have filed a patent for the molecule. The next step will be to perform clinical trials in humans.

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“The new PET ligand could help us to research ALS more effectively and to understand how the disease progresses,” says Ametamey.

It could also improve the early diagnosis of the disease. It might also be potentially interesting for research and diagnosis of other neurological disorders, such as Alzheimer’s, Parkinson’s, or multiple sclerosis.

Potential treatment?

One of the drawbacks of the new PET ligand is that it is based on the carbon-11 radioisotope, which has a very short half-life of around 20 minutes.

“This means the substance can only be used in the location where it is produced,” he says. Ametamey’s team is refining the new marker substance and incorporating the fluorine-18 radioisotope, which has a half-life of 110 minutes. They’ve reported some initial success.

The molecule could also have therapeutic potential in a derivative, non-radioactive form. “Substances that bind to CNR2 produce an anti-inflammatory effect in the body,” he confirms. “It might therefore be possible to use related molecules to treat ALS and other neuroinflammatory diseases.”

The Swiss ALS Foundation and the Vontobel Foundation supported the project.

Source: ETH Zurich

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