Sun Yang, Rodríguez-Rangel Sofia, Zhang Lauren L, Sánchez-Rodríguez Jorge E, Brugarolas Pedro
Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Departamento de Física, Universidad de Guadalajara, Guadalajara, Jalisco 44430, México.
bioRxiv. 2023 Aug 9:2023.08.08.550404. doi: 10.1101/2023.08.08.550404.
4-aminopyridine (4AP) is a potassium (K) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K channels in demyelinated axons, reducing the leakage of intracellular K and enhancing impulse conduction. Multiple derivatives of 4AP capable of blocking K channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (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 the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP is more lipophilic (logD = 0.664 ± 0.005 0.414 ± 0.002) and slightly more basic (p = 7.46 ± 0.01 . 7.37 ± 0.07). In addition, 5Me3F4AP appears to be more permeable to an artificial brain membrane and more 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.
4-氨基吡啶（4AP）是一种钾（K）通道阻滞剂，临床上用于改善多发性硬化症（MS）患者的行走能力。4AP与脱髓鞘轴突中暴露的K通道结合，减少细胞内K的泄漏并增强冲动传导。已报道了多种能够阻断K通道的4AP衍生物，包括三种用正电子发射同位素标记的衍生物，用于使用正电子发射断层扫描（PET）对脱髓鞘病变进行成像。在此，我们描述了3-氟-5-甲基吡啶-4-胺（5Me3F4AP），一种具有PET潜在应用价值的新型K通道阻滞剂。5Me3F4AP的效力与4AP和PET示踪剂3-氟-4-氨基吡啶（3F4AP）相当。与3F4AP相比，5Me3F4AP具有更高的亲脂性（logD = 0.664 ± 0.005对0.414 ± 0.002）且碱性略强（pKa = 7.46 ± 0.0１对7.37 ± 0.07）。此外，5Me3F4AP似乎对人工脑膜具有更高的渗透性，并且对细胞色素P450酶家族2亚家族E成员1（CYP2E1）介导的氧化更稳定，CYP2E1负责4AP和3F4AP的代谢。综上所述，5Me3F4AP具有用于PET成像的良好特性，值得进一步研究。
