Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Departamento de Física, Universidad de Guadalajara, Guadalajara, Jalisco, 44430, México.
Sci Rep. 2024 May 15;14(1):11105. doi: 10.1038/s41598-024-61465-w.
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 (pK = 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 (P = 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 (IC = 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.
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 的渗漏，增强冲动传导。已经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 4AP，用于使用正电子发射断层扫描（PET）成像脱髓鞘病变。然而，仍然需要具有合适物理化学性质和结合亲和力的新型分子，这些分子有可能被放射性标记并用作 PET 放射性示踪剂。在这项研究中，我们引入 3-氟-5-甲基吡啶-4-胺（5Me3F4AP）作为一种新型的三取代 K 通道阻滞剂，具有在 PET 中的潜在应用。5Me3F4AP 与 4AP 和 PET 示踪剂 3-氟-4-氨基吡啶（3F4AP）具有相当的效力。与 3F4AP 相比，5Me3F4AP 具有相当的碱性（pK = 7.46 ± 0.01 与 7.37 ± 0.07，P 值 = 0.08），更高的亲脂性（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（P = 88.1 ± 18.3 与 31.1 ± 2.9 nm/s，P 值 = 0.03）。5Me3F4AP 对细胞色素 P450 酶 CYP2E1 的氧化也更稳定（IC = 36.2 ± 2.5 与 15.4 ± 5.1，P 值 = 0.0003）；CYP2E1 是负责 4AP 和 3F4AP 代谢的酶。总之，5Me3F4AP 具有作为 PET 成像候选物的有前途的特性，值得进一步研究。
