Abstract
4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 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 (-CH3), methoxy (-OCH3) as well as trifluoromethyl (-CF3) 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 3CF34AP) were found to be about 3- to 4-fold less potent than 4AP; and 2-trifluoromethyl-4-AP (2CF34AP) was found to be about 60-fold less active. These results suggest that these novel derivatives are potential candidates for therapy and imaging.
Highlights
4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS)
In terms of lipophilicity 4AP, 3Me4AP, and 3MeO4AP were found to have octanol/water partition coefficient values at pH 7.4 of −1.48, −1.23 and −0.76 (Table 1). This indicates that these compounds preferably partition in the aqueous layer and may have lower penetration of the blood-brain barrier (BBB) by passive diffusion
3F4AP, 2CF34AP and 3CF34AP show partition coefficient values of 0.41, 1.48 and 0.91 (Table 1) indicating that these compounds preferably partition in the octanol layer and may have a faster permeation of the BBB
Summary
4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). Given the correlations between the pKa, lipophilicity and molecular size with in vivo activity, we hypothesized that the derivatives 3-methyl-4-aminopyridine (3Me4AP), 3-methoxy-4-aminopyridine (3MeO4AP), 3-trifluoromethyl-4-aminopyridine (3CF34AP) and 2-trifluoromethyl-4-aminopyridine (2CF34AP) would be permeable to the CNS and be suitable candidates for therapy and/or imaging (Fig. 2A). These molecules are interesting as potential PET radioligands since they are amenable to labeling with 11C, which provides. Methods to produce radiolabeled [11C]3MeO4AP, [11C]2CF34AP and [11C]3CF34AP46,47 have recently been communicated but evidence that these compounds are able to bind to KV channels is lacking
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
