Demyelination, the loss of the insulating sheath of neurons, causes failed or slowed neuronal conduction and contributes to the neurological symptoms in multiple sclerosis, traumatic brain and spinal cord injuries, stroke, and dementia. In demyelinated neurons, the axonal potassium channels Kv1.1 and Kv1.2, generally under the myelin sheath, become exposed and upregulated. Therefore, imaging these channels using positron emission tomography can provide valuable information for disease diagnosis and monitoring. Here, we describe a novel tracer for Kv1 channels, [11C]3-methyl-4-aminopyridine ([11C]3Me4AP). [11C]3Me4AP was efficiently synthesized via Pd(0)-Cu(I) comediated Stille cross-coupling of a stannyl precursor containing a free amino group. Evaluation of its imaging properties in rats and nonhuman primates showed that [11C]3Me4AP has a moderate brain permeability and slow kinetics. Additional evaluation in monkeys showed that the tracer is metabolically stable and that a one-tissue compartment model can accurately model the regional brain time-activity curves. Compared to the related tracers [18F]3-fluoro-4-aminopyridine ([18F]3F4AP) and [11C]3-methoxy-4-aminopyridine ([11C]3MeO4AP), [11C]3Me4AP shows lower initial brain uptake, which indicates reduced permeability to the blood-brain barrier and slower kinetics, suggesting higher binding affinity consistent with in vitro studies. While the slow kinetics and strong binding affinity resulted in a tracer with less favorable properties for imaging the brain than its predecessors, these properties may make 3Me4AP useful as a therapeutic.
Keywords: K+ channels; PET; Stille reaction; carbon-11; demyelination; pharmacokinetics.