A New Method to Develop PET Ligands for Protein Aggregates in Neurodegenerative Disorders Using Soluble Brain-Derived Aggregates

阿尔茨海默氏症、帕金森氏病和亨廷顿氏病等所有痴呆症的一个共同特征是大脑中存在特定的蛋白质，由于结构异常，这些蛋白质积累成越来越大的组件和纤维。这些结构存在于大脑的许多区域，被认为是有毒的，会损害脑细胞，导致痴呆症的症状。利用正电子发射断层扫描(PET)的临床脑成像技术，结合向患者体内注射选择性地与这些组装结合的化学探针，我们现在可以可视化一些有毒蛋白质的存在和分布。然而，以目前这些化学探针的范围，我们只能想象这些组件的后期阶段，那时大多数脑损伤已经发生，因此已经太晚了，无法进行有效的药物治疗。因此，我们的目标是开发一种通用的方法来寻找下一代化学探针，当这些异常蛋白质被认为毒性最大，从而对脑细胞造成最大损害时，可以成像这些异常蛋白质的早期阶段和结构。这将为更早、更准确地诊断痴呆症创造一种强大的手段，并为评估针对这些组件开发的新型药物提供一种手段。为此，我们将从不幸死于神经退行性疾病的患者的脑组织样本中提取少量可溶的有毒聚集体，并使用我们开发的一种可以检测单个聚集体的非常敏感的荧光方法，直接成像标记探针与这些聚集体的结合。这种方法将直接测试与人体聚集体的结合，只需要非常少量的试剂。一旦我们有了与可溶聚集体结合的探针，我们就可以看看其他未标记的潜在探针是否能将它们移除，从而更快地筛选出更好的探针，这些探针将在人类身上发挥作用，并可用于检测疾病早期形成的聚集体。

A common feature of all dementias e.g. Alzheimer's, Parkinson's and Huntington's diseases are the presence of specific proteins in the brain, which due to having abnormal structures, accumulate into increasingly large assemblies and fibrils. These structures, which are present in many regions of the brain, are considered to be toxic and damage brain cells, leading to the symptoms of dementia. Using the clinical brain imaging technique of Positron Emission Tomography (PET) combined with injecting into patients chemical probes, which selectively bind to these assembles, we can now visualize the presence and distribution of some of these toxic proteins. However, with the present range of these chemical probes we can only image the late stages of these assemblies when most of the brain damage has occurred and so too late for effective drugs therapies. Therefore, our aim is to develop a general method to find the next generation chemical probes that can image the earlier stages and structures of these abnormal proteins when they are considered most toxic and hence cause the most damage to brains cells. This would then create a powerful means for earlier more accurate diagnosis of dementia and a means of evaluating the new types of drugs that are been developed that target these assemblies. To do this we will extract small amounts of soluble toxic aggregates from samples of brain tissue from patients who unfortunately died with a neurodegenerative disease and directly image the binding of labelled probes to these aggregates, using a very sensitive fluorescence method that we have developed that can detect single aggregates. This method will directly test binding to the aggregates in humans and needs only very small amounts of reagents. Once we have probes that bind to the soluble aggregates we can see if other unlabelled potential probes can remove them and hence more rapidly screen for better probes that will work in humans and can be used to detect the aggregates formed at early stages of disease.