Fluorinated 4-Aminopyridines for Therapy and Diagnosis of Multiple Sclerosis

描述（由申请人提供）：目前，多发性硬化症（MS）的诊断和监测是基于mri辅助的临床评估。虽然MRI提供了很大的空间分辨率，但MRI上的信号是非特异性的，很难解释。相比之下，PET成像更加敏感和特异。因此，采用PET示踪剂作为MS的补充是非常理想的。目前，正在调查的MS5-7的PET标记物很少，临床也没有。4-氨基吡啶（Ampyra(r), 4-AP）是最近批准的一种用于多发性硬化症的药物，被认为与脱髓鞘病变中新暴露的K+通道结合8。我们有证据表明，脱髓鞘白质区域的4-AP摄取高于正常髓鞘区域，这表明4-AP的PET活性衍生物可以作为脱髓鞘的PET示踪剂。我们也有证据表明，我们设计的两种4-AP的氟化类似物与4-AP具有非常相似的生物学特性，这表明，一旦用氟-18标记，这些分子可以成为脱鞘的优秀PET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追踪MS动物模型的无创脱髓鞘。如果正如我们预测的那样，这些示踪剂有效地定位于脱髓鞘轴突，它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通道具有相似的亲和力，并且具有更大的脑通透性和代谢稳定性，这表明这些分子可能是比4-AP更优越的治疗药物（更安全或更有效），目前4-AP仅使约三分之一的MS患者受益。因此，在本项目的第一部分，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多发性硬化症患者恢复神经功能。

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.