PET Markers of Oligomeric Misfolded Proteins in Neurodegenerative Disorders

神经退行性疾病中寡聚错误折叠蛋白的 PET 标记

• 批准号: EP/P008224/1
• 负责人: Franklin Aigbirhio
• 金额: $ 132.75万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FP008224%2F1
• 关键词: PET; Markers; Oligomeric; Misfolded; Proteins

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.

所有痴呆例如阿尔茨海默病、帕金森病和亨廷顿病的共同特征是脑中存在特定蛋白质，其由于具有异常结构而积累成越来越大的组装体和原纤维。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。使用正电子发射断层扫描（PET）的临床脑成像技术，结合向患者注射选择性结合这些组装的化学探针，我们现在可以可视化这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，我们只能在大部分脑损伤发生时对这些组装的晚期进行成像，因此对于有效的药物治疗来说为时已晚。因此，我们的目标是开发下一代化学探针，可以对这些异常蛋白质的早期阶段和结构进行成像，因为它们被认为是毒性最大的，因此对脑细胞造成的损害最大。这将为早期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，放射化学和生物评估。我们会为这项计划所产生的具有适当性质的化学探针提供额外资金，以进行人体成像研究。

项目成果

Detection and Characterization of Small Molecule Interactions with Fibrillar Protein Aggregates Using Microscale Thermophoresis.

使用微尺度热泳法检测和表征小分子与纤维状蛋白聚集体的相互作用。

• DOI: 10.1021/acschemneuro.7b00228
• 发表时间: 2017
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: Fisher E

[18F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia

[18F]AV-1451 体内结合反映了原发性进行性失语症语义变异中 TDP-43 病理学的预期分布

• DOI: 10.17863/cam.13435
• 发表时间: 2018
• 作者: Bevan-Jones W

Extrinsic Amyloid-Binding Dyes for the Detection of Individual Protein Aggregates in Solution

用于检测溶液中单个蛋白质聚集体的外源淀粉样蛋白结合染料

• DOI: 10.17863/cam.32015
• 发表时间: 2018
• 作者: Klenerman D

Development and Application of Imaging Probes for Molecular Imaging by Positron Emission Tomography

正电子发射断层扫描分子成像成像探针的研制与应用

• DOI: 10.33774/coe-2022-g3hwc
• 发表时间: 2022
• 作者: Aigbirhio F