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4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (K
1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [
F]3F4AP, a radiofluorinated analog of 4AP, also binds to K
1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate four novel 4AP derivatives containing methyl (-CH
), methoxy (-OCH
) as well as trifluoromethyl (-CF
) in the 2 and 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (basicity and lipophilicity) and analyzed their ability to block Shaker K
channel under different voltage and pH conditions. Our results demonstrate that three of the four derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP and 3F4AP; 3-methoxy- and 3-trifluoromethyl-4-aminopyridine (3MeO4AP and 3CF
4AP) were found to be about 3- to 4-fold less potent than 4AP; and 2-trifluoromethyl-4-AP (2CF
4AP) was found to be about 60-fold less active. These results suggest that these novel derivatives are potential candidates for therapy and imaging.