Fluorinated 4-Aminopyridines for Therapy and Diagnosis of Multiple Sclerosis

University Of Chicago, Chicago IL

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Currently, the diagnosis and monitoring of multiple sclerosis (MS) are based on clinical evaluation aided by MRI3. Although MRI offers great spatial resolution, the signal on an MRI is non-specific and it can be difficult to interpret. In compariso, PET imaging is much more sensitive and specific4. It would therefore be ideal to have a PET tracer for MS to complement MRI. At present, there are very few PET markers under investigation for MS5-7 and none in the clinic. 4-aminopyridine (Ampyra(r), 4-AP) is a recently approved drug for MS that is believed to bind to newly exposed K+ channels in demyelinated lesions8. We have evidence that there is a higher uptake of 4-AP in demyelinated white matter areas than in normally myelinated areas suggesting that a PET-active derivative of 4-AP could serve as a PET tracer for demyelination. We also have evidence that two fluorinated analogs of 4-AP that we designed have very similar biological properties as 4-AP suggesting that, once labeled with fluorine-18, these molecules could be excellent PET tracers for demyelination. In this project we propose to generate these molecules and test if they can be used to trace demyelination in animal models of MS non-invasively. If, as we predict, these tracers effectively localize to demyelinated axons, it would provide clinicians with an unprecedented method to image the key pathologic event responsible for MS symptoms. In addition, our data shows that these fluorinated derivatives have similar affinity to Kv1 channels and possess greater brain permeability and metabolic stability suggesting that these molecules may be superior therapeutics to 4-AP (safer or more effective), which currently only benefits about one third of MS patients. Therefore in the first part of this project we propose to compare the beneficial effects of these drugs on the neurological function of mouse models of demyelination. If successful, these drugs could help restore neurological function in a greater number of people with MS.