PDF(Pubmed)
Abstract：
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). 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+ 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 (pKa = 7.46 ± 0.01 vs. 7.37 ± 0.07, P-value = 0.08), greater lipophilicity (logD = 0.664 ± 0.005 vs. 0.414 ± 0.002, P-value < 0.0001) and higher permeability to an artificial brain membrane (Pe = 88.1 ± 18.3 vs. 31.1 ± 2.9 nm/s, P-value = 0.03). 5Me3F4AP is also more stable towards oxidation in vitro by the cytochrome P450 enzyme CYP2E1 (IC50 = 36.2 ± 2.5 vs. 15.4 ± 5.1, P-value = 0.0003); 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.
摘要：
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。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，增强冲动传导。已经报道了能够阻断K通道的4AP的多种衍生物，包括三种用正电子发射同位素放射性标记的，用于使用正电子发射断层扫描（PET）对脱髓鞘病变进行成像。然而,仍然需要具有合适的物理化学性质和结合亲和力的新型分子,其可以潜在地被放射性标记并用作PET放射性示踪剂。在这项研究中,我们介绍了3-氟-5-甲基吡啶-4-胺（5Me3F4AP）作为一种新型的三取代K通道阻断剂，在PET中具有潜在的应用。5Me3F4AP具有与4AP和PET示踪剂3-氟-4-氨基吡啶(3F4AP)相当的效力。与3F4AP相比，5Me3F4AP表现出可比的碱度（pKa=7.46±0.01与7.37±0.07，P值=0.08），更大的亲脂性（logD=0.664±0.005与0.414±0.002，P值<0.0001）和更高的人工脑膜通透性（Pe=88.1±18.3vs.31.1±2.9nm/s,P值=0.03)。5Me3F4AP对细胞色素P450酶CYP2E1的体外氧化也更稳定（IC50=36.2±2.5vs.15.4±5.1，P值=0.0003）；负责4AP和3F4AP代谢的酶。一起来看,5Me3F4AP作为PET成像的候选物具有有希望的特性，需要进一步的研究。
