(4AP) is a specific blocker of voltage-gated potassium channels (K V 1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [ 18 F]3F4AP, a radiofluorinated analog of 4AP, also binds to K V 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 3), methoxy (-OCH 3) as well as trifluoromethyl (-CF 3) 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 3 4AP) were found to be about 3-to 4-fold less potent than 4AP; and 2-trifluoromethyl-4-AP (2CF 3 4AP) was found to be about 60-fold less active. these results suggest that these novel derivatives are potential candidates for therapy and imaging.

4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (K V 1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [ 18 F]3F4AP, a radiofluorinated analog of 4AP, also binds to K V 1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate three novel 4AP derivatives containing methyl (-CH 3 ), methoxy (-OCH 3 ) and trifluoromethyl (-CF 3 ) in the 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (pK a and logD) and analyzed their ability to block Shaker K + channel under different voltage and pH conditions. Our results demonstrate that all three 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, whereas the methoxy (3MeO4AP) and trifluoromethyl (3CF 3 4AP) containing compounds were about 3-to 4-fold less potent than 4AP, respectively. These results suggest that these novel derivatives are potential candidates for therapy and imaging.

4-aminopyridine (4AP) is a potassium (K+) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). Multiple derivatives of 4AP capable of blocking K+ channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using PET. Here, we describe 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP), a novel K+ channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP is more lipophilic (logD = 0.664 ± 0.005 vs. 0.414 ± 0.002) and slightly more basic (pKa = 7.46 ± 0.01 vs. 7.37 ± 0.07). In addition, 5Me3F4AP appears to be more permeable to an artificial brain membrane and stable towards oxidation by the cytochrome P450 enzyme family 2 subfamily E member 1 (CYP2E1), responsible for the metabolism of 4AP and 3F4AP. Taken together, 5Me3F4AP has promising properties for PET imaging warranting additional investigation.