Fluorinated 4-Aminopyridines for Therapy and Diagnosis of Multiple Sclerosis

用于治疗和诊断多发性硬化症的氟化 4-氨基吡啶

• 批准号: 8800583
• 负责人: Brian J Popko
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800583
• 关键词: 4-Aminopyridine; Address; Affinity; Animal Model; Animals; Area; Autoradiography; Axon; Binding; Biological; Biological Assay; Brain; Clinic; Clinical; Complement; Data; Demyelinations; Development; Diagnosis; Evaluation; Event; Fluorine; Goals; Health; Image; Investigation; Label; Length; Lesion; Magnetic Resonance Imaging; Metabolic; Methods; Monitor; Multiple Sclerosis; Myelin Sheath; Nerve; Nervous System Physiology; Pathologic; Pathology; Patients; Permeability; Pharmaceutical Preparations; Positron-Emission Tomography; Potassium; Potassium Channel; Property; Proteins; Radiolabeled; Reading; Relative (related person); Resolution; Signal Transduction; Symptoms; Testing; Therapeutic; Tracer; analog; base; clinically relevant; design; imaging probe; in vivo; mouse model; neuropathology; radiotracer; research clinical testing; uptake; voltage clamp; white matter

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.

描述（由申请人提供）：目前，多发性硬化症（MS）的诊断和监测基于MRI3的临床评估。尽管MRI提供了很好的空间分辨率，但MRI上的信号是非特异性的，可能很难解释。相比之下，PET成像更敏感和特异性4。因此，有一个宠物示踪剂供MS补充MRI是理想的选择。目前，MS5-7的宠物标记很少，在诊所中没有宠物标记。 4-氨基吡啶（Ampyra（R），4-AP）是最近经过批准的MS药物，据信它与脱髓鞘病变中的新暴露的K+通道结合。我们有证据表明，脱髓白质区域的4AP吸收要比正常骨髓的区域更高，这表明4-AP的宠物活性衍生物可以作为脱髓鞘的宠物示踪剂。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4AP非常相似的生物学特性，表明一旦用氟-18标记，这些分子可能是脱髓鞘的出色宠物示踪剂。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在MS非侵入性的动物模型中追踪脱髓鞘。正如我们预测的那样，这些示踪剂有效地定位于脱髓鞘的轴突，它将为临床医生提供前所未有的方法，以对负责MS症状的关键病理事件进行成像。 此外，我们的数据表明，这些氟化衍生物与KV1通道具有相似的亲和力，并且具有更大的脑部渗透性和代谢稳定性，这表明这些分子可能是优质的治疗疗法，而疗法可以比4-AP（更安全或更有效），目前仅受益于大约三分之一的MS患者。因此，在本项目的第一部分中，我们建议将这些药物对小鼠脱髓鞘模型的神经功能的有益作用进行比较。如果成功的话，这些药物可以帮助恢复更多具有MS的人的神经功能。