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A new radiolabeled molecule could help scientists track the fate of drug candidates for neurodegenerative illnesses like Alzheimer’s disease and Huntington’s disease using positron emission tomography (PET). The PET tracer, called 18F-cholestify, reveals expression of cytochrome P450 46A1 (CYP46A1), a cholesterol-degrading enzyme in the brain (Sci. Trans. Med. 2022, DOI: 10.1126/scitranslmed.adc9967).
CYP46A1 oxidizes cholesterol in the brain, making a cholesterol derivative that can go through the blood-brain barrier so that it can be transported out of the central nervous system. Scientists have suspected that neurodegenerative diseases can be linked to CYP46A1 gone awry, but they haven’t had a way to study the enzyme in living brains.
Seeking a way to do just that, a team led by Emory University’s Steven H. Liang developed 18F-Cholestify to bind to CYP46A1. In PET scans in mice, nonhuman primates, and people, the tracer illuminates areas of the brain where CYP46A1 is expressed. The chemical probe “can give us real-time information,” Liang says. 18F-Cholestify can also help drugmakers test how well drug candidates engage CYP46A1 in the brain, he adds.
Comparing the enzyme’s expression in brains of healthy people with its expression in the brains of people with neurodegenerative diseases could reveal CYP46A1’s role in those conditions. Observing how CYP46A1 is expressed in the brains of people of different ages could also shed light on how the enzyme changes as people age.
Liang’s team found 18F-Cholestify showed a stronger signal in mice engineered to have Alzheimer’s disease compared with control mice. In a study of eight healthy people, 18F-Cholestify revealed that women had a greater expression of CYP46A1 than men of the same age.
The study provides “strong evidence linking brain cholesterol dysregulation to neurological disease,” says Hank F. Kung, an expert in radiotracers at the University of Pennsylvania, in an email. “This paper highlights an enzymatic process in the brain that could be unwittingly associated with risks of developing neurodegenerative diseases,” he says, noting that “further studies in humans will be needed to determine the relationship between changes observed by PET imaging with different brain diseases.”
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