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COX-2 radiotracer could pinpoint very early stages of neurodegenerative diseases

Tracking tool’s strong signal reveals brain inflammation in positron-emission tomography scans

by Louisa Dalton, special to C&EN
May 10, 2024


Molecular structure of [11C]BRD1158 and [11C]MC1 with radiolabels marked in red in the form of carbon-11 atoms. The molecules differ in the placement of the radiolabel, with a methylsulfonyl group labeled in BRD1158 and a methoxy group labeled in MC1.

Researchers have few tools for understanding what happens in the brain at the earliest stages of neuroinflammatory disorders such as Alzheimer’s or Huntington’s disease. A new signaling molecule that homes in on inflammation could facilitate tracking and treatment of early neurological inflammation and the disorders that follow (ACS Cent. Sci. 2024, DOI: 10.1021/acscentsci.3c01564).

One of the enzymes that triggers inflammation, cyclooxygenase-2 (COX-2), often peaks promptly and quickly fades away. Its transitory nature makes it a handy tracker for pinpointing wherever inflammation pops up. And if researchers can locate recurring inflammation, they can also detect when and where neurological diseases are starting to take hold. Scientists can then study those early stages, when there is still time to administer therapeutics to protect the brain.

A number of laboratories have designed molecules that bind to COX-2 and reveal its location via positron-emission tomography (PET). One of the best so far, carbon-11-labeled MC1 ([11C]MC1), has enabled the imaging of COX-2 in healthy human brains. “It’s a brilliant tracer,” says Jacob Hooker, a radiochemist at Mass General Research Institute, “and very potent, if it has time.”

PET radiotracers need to bind to their target within a matter of minutes, before the body clears out any unbound tracer. So the faster a PET radiotracer binds, the stronger its signal and the greater its ability to locate even lower numbers of its target molecule, Hooker adds.

Hooker and his team members suspected that if they could tailor MC1, which already has a high affinity for COX-2, to bind faster, they would improve its COX-2 sensitivity. The group snipped and altered the tracer and then tested each tweaked molecule for COX-2 binding speed. Looking for those compounds that bind to COX-2 within 2–10 min, the researchers ended up with a few alternatives to MC1 that bind quickly and release quickly, including a molecule called BRD1158.

After labeling their fastest-binding compounds with carbon-11, the researchers tested the molecules in rats injected with a virus engineered to express COX-2. They found that the strongest signal from [11C]BRD1158 showed up between 10 and 20 min. That’s compared with [11C]MC1’s signal, which lit up brightest between minutes 30 and 40.

The faster signaling of [11C]BRD1158 in the rat model suggests that the tracer should bind quickly during human PET scans. That would mean it could reveal areas with lower COX-2 concentration before getting cleared from the body, Hooker says.

Hooker thinks [11C]BRD1158 will give researchers a chance to image inflammation in the brain that no other tracer yet can. He’ll be testing the tracer in patients with Huntington’s disease by the end of the year.

J. John Mann, who studies molecular imaging and neuropathology at Columbia University, says this faster tracer has promise. But it’s not yet clear to him how sensitive the PET tracer is at detecting the presence of COX-2. Until human studies are conducted, “we have no idea,” he says. He adds that a good COX-2 radiotracer could illuminate not just brain inflammation but inflammation due to cancer, rheumatoid arthritis, or even transplant rejection.


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