PET Markers of Oligomeric Misfolded Proteins in Neurodegenerative Disorders

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物结合的化学探针，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。为了发现和开发这些新的化学探针，将应用化学筛选方法、药物化学、放射化学和生物学评估。从这个项目中产生的具有适当性质的化学探针，我们将继续为人体成像研究提供额外的资金。

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 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 discover and develop these new chemical probes, will apply chemical screening methods, medicinal chemistry, radiochemistry and biological assessments. The chemical probes with appropriate properties arising from this project we would then take forward with additional funding for human imaging studies.