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Multiple derivatives of 4AP capable of blocking K\n                    <jats:sup>+<\/jats:sup>\n                    channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (PET). However, there remains a demand for novel molecules with suitable physicochemical properties and binding affinity that can potentially be radiolabeled and used as PET radiotracers. In this study, we introduce 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP) as a novel trisubstituted K\n                    <jats:sup>+<\/jats:sup>\n                    channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP exhibits comparable basicity (p\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>a<\/jats:sub>\n                    \u2009=\u20097.46\u2009\u00b1\u20090.01 vs. 7.37\u2009\u00b1\u20090.07, P-value\u2009=\u20090.08), greater lipophilicity (logD\u2009=\u20090.664\u2009\u00b1\u20090.005 vs\n                    <jats:italic>.<\/jats:italic>\n                    0.414\u2009\u00b1\u20090.002, P-value\u2009&lt;\u20090.0001) and higher permeability to an artificial brain membrane (\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>e<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u200988.1\u2009\u00b1\u200918.3 vs\n                    <jats:italic>.<\/jats:italic>\n                    31.1\u2009\u00b1\u20092.9\u00a0nm\/s, P-value\u2009=\u20090.03). 5Me3F4AP is also more stable towards oxidation in vitro by the cytochrome P450 enzyme CYP2E1 (\n                    <jats:italic>IC<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>50<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009=\u200936.2\u2009\u00b1\u20092.5 vs\n                    <jats:italic>.<\/jats:italic>\n                    15.4\u2009\u00b1\u20095.1, P-value\u2009=\u20090.0003); the enzyme responsible for the metabolism of 4AP and 3F4AP. Taken together, 5Me3F4AP has promising properties as a candidate for PET imaging warranting additional investigation.\n                  <\/jats:p>","DOI":"10.1038\/s41598-024-61465-w","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T04:04:28Z","timestamp":1715745868000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chemical and biophysical characterization of novel potassium channel blocker 3-fluoro-5-methylpyridin-4-amine"],"prefix":"10.1038","volume":"14","author":[{"given":"Yang","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Rodr\u00edguez-Rangel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren L.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8747-7239","authenticated-orcid":false,"given":"Jorge E.","family":"S\u00e1nchez-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7455-2743","authenticated-orcid":false,"given":"Pedro","family":"Brugarolas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,5,15]]},"reference":[{"key":"61465_CR1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1002\/ana.410210113","volume":"21","author":"D Stefoski","year":"1987","unstructured":"Stefoski, D., Davis, F. 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