Abstract
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Objectives Focal demyelinated lesions in the brain represent the pathological hallmark of multiple sclerosis (MS). Imaging in MS is dominated by MRI, which is not specific or quantitative for changes in myelination. PET tracers that bind to demyelinated axons may provide a more specific means to diagnose and monitor changes in this disease. Here, we explore the possibility that an 18F-labeled derivative of 4-aminopyridine (4AP), a K+ channel blocker used clinically to improve walking in people with MS, can serve as a PET tracer. Specifically, we seek to: - Verify that 4AP has higher uptake in demyelinated vs. myelinated areas in animal models of MS. - Develop a fluorinated derivative of 4AP, named 3F4AP, compatible with F-18 labeling - Conduct PET imaging studies using [18F]3F4AP
Methods - Ex vivo C-14 autoradiography to evaluate the tracer distribution in the brain of mouse models of MS - Biochemical assays to find fluorinated 4AP analogs and characterize their binding affinity and stability - Radiochemical synthesis to prepare [18F]3F4AP - PET imaging and gamma counting in rodents to characterize the tracer in vivo - PET imaging in non-human primates is ongoing
Results Using C-14 autoradiography, we found that 4AP and the fluorinated derivative, 3F4AP, show significantly higher uptake in demyelinated over normally myelinated white matter and can distinguish demyelinated versus control mice. A method for preparing [18F]3F4AP has been developed utilizing aromatic nucleophilic substitution followed by reduction. A 30 min dynamic PET scan in healthy rats showed that the tracer localizes primarily in non-myelinated areas of the brain with a mean whole brain SUV of 2.91.
Conclusions We have developed the first PET tracer whose binding increases in demyelinated brain regions. [18F]3F4AP is metabolically stable and is based on an approved MS drug. Thus, this compound is a promising PET tracer for demyelinating conditions.
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