Fluorinated 4-Aminopyridines for Therapy and Diagnosis of Multiple Sclerosis

描述(申请人提供)：目前，多发性硬化症(MS)的诊断和监测是基于MRI3辅助的临床评估。虽然核磁共振成像提供了很高的空间分辨率，但核磁共振成像上的信号是非特异性的，可能很难解释。相比之下，正电子发射计算机断层扫描要敏感得多，也更具特异性。因此，理想的做法是为MS提供一种PET示踪剂来补充MRI。目前，对MS5-7进行研究的PET标志物很少，临床上还没有。4-氨基吡啶(Ampyra(R)，4-AP)是最近批准的一种治疗多发性硬化的药物，据信它能与脱髓鞘病变中新暴露的K+通道结合。我们有证据表明，4-AP在脱髓鞘白质区域的摄取比在正常髓鞘区域更高，这表明4-AP的PET活性衍生物可以作为脱髓鞘的PET示踪剂。我们还有证据表明，我们设计的两个4-AP的氟化类似物具有与4-AP非常相似的生物学特性，这表明，一旦用氟-18标记，这些分子可能是优秀的PET脱髓鞘示踪剂。在这个项目中，我们建议生成这些分子，并测试它们是否可以用于无创追踪多发性硬化症动物模型的脱髓鞘。如果如我们预测的那样，这些示踪剂有效地定位于脱髓鞘轴突，这将为临床医生提供一种前所未有的方法来成像导致MS症状的关键病理事件。此外，我们的数据显示，这些氟化衍生物与KV1通道具有类似的亲和力，并具有更高的脑通透性和代谢稳定性，这表明这些分子可能是优于4-AP(更安全或更有效)的治疗药物，后者目前仅使大约三分之一的MS患者受益。因此，在这个项目的第一部分，我们建议比较这些药物对脱髓鞘小鼠模型神经功能的有益影响。如果成功，这些药物可以帮助更多的MS患者恢复神经功能。

DESCRIPTION (provided by applicant): Currently, the diagnosis and monitoring of multiple sclerosis (MS) are based on clinical evaluation aided by MRI3. Although MRI offers great spatial resolution, the signal on an MRI is non-specific and it can be difficult to interpret. In compariso, PET imaging is much more sensitive and specific4. It would therefore be ideal to have a PET tracer for MS to complement MRI. At present, there are very few PET markers under investigation for MS5-7 and none in the clinic. 4-aminopyridine (Ampyra(r), 4-AP) is a recently approved drug for MS that is believed to bind to newly exposed K+ channels in demyelinated lesions8. We have evidence that there is a higher uptake of 4-AP in demyelinated white matter areas than in normally myelinated areas suggesting that a PET-active derivative of 4-AP could serve as a PET tracer for demyelination. We also have evidence that two fluorinated analogs of 4-AP that we designed have very similar biological properties as 4-AP suggesting that, once labeled with fluorine-18, these molecules could be excellent PET tracers for demyelination. In this project we propose to generate these molecules and test if they can be used to trace demyelination in animal models of MS non-invasively. If, as we predict, these tracers effectively localize to demyelinated axons, it would provide clinicians with an unprecedented method to image the key pathologic event responsible for MS symptoms. In addition, our data shows that these fluorinated derivatives have similar affinity to Kv1 channels and possess greater brain permeability and metabolic stability suggesting that these molecules may be superior therapeutics to 4-AP (safer or more effective), which currently only benefits about one third of MS patients. Therefore in the first part of this project we propose to compare the beneficial effects of these drugs on the neurological function of mouse models of demyelination. If successful, these drugs could help restore neurological function in a greater number of people with MS.