Blood-Brain Barrier Permeable Multimodal Imaging Agents for Neurodegenerative Diseases

项目摘要/摘要 多肽和蛋白质的聚集在许多毁灭性的神经退行性疾病中起着关键作用， 包括阿尔茨海默病(AD)和其他与AD相关的痴呆(ADRD)，如路易体痴呆(LBD) 额颞部退行性变(FTD)以及帕金森氏病(PD)和肌萎缩侧索硬化症 (ALS)。在这些淀粉样变性或蛋白质病中，阿尔茨海默病(AD)是最常见的 神经退行性疾病是美国第六大致死原因。大约有600万人 目前在美国被诊断为阿尔茨海默病，预计到2050年这一数字将达到1400万。到目前为止在那里 阿尔茨海默病没有疾病修正治疗，其高准确率的诊断需要详细的尸检 对大脑的检查。阿尔茨海默病的主要神经病理特征是淀粉样斑块的沉积 由淀粉样β蛋白(A-β)多肽组成的新的治疗靶点还包括磷酸化tau(p-tau) 聚集，以及活性氧物种(ROS)的产生，神经炎症和氧化应激。 因此，有一个巨大的未得到满足的需求，即开发能够在早期阶段检测到 与蛋白质病有关的各种淀粉样蛋白的寡聚体的形成(如Aβ和 AD中的P-tau和PD中的α-突触核蛋白)，以及靶向这些疾病的其他特征，如 神经炎症和氧化应激。在这里，我们计划使用基本的化学方法来 新型血脑屏障透过性多功能双PET/MRI显像剂的研制及临床评价 他们作为AD和ADRD的诊断试剂的能力。在这些研究中，我们将使用新的有机和 无机化学设计原理和合成方法，以及详细的表征 开发了用于成像/诊断应用的生物无机系统。所有已提交研究的进展 方向将导致新的诊断试剂的开发和优化，以促进人类健康。

Project Summary / Abstract The aggregation of peptides and proteins plays a key role in many devastating neurodegenerative disorders, including Alzheimer's disease (AD) and other AD-related dementias (ADRD) such as Lewy Body dementia (LBD) and Frontotemporal degeneration (FTD), as well as Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Among these amyloid disorders or proteinopathies, Alzheimer's disease (AD) is the most common neurodegenerative disease and the sixth leading cause of death in United States. Around 6 million people are presently diagnosed with AD in the US, and the number is expected to reach 14 million by 2050. To date there is no disease-modifying treatment for AD and its diagnosis with high accuracy requires a detailed post-mortem examination of the brain. While the main neuropathological hallmark of AD is the deposition of amyloid plaques comprising the amyloid beta (Aβ) peptide, new therapeutic targets also include the phosphorylated tau (p-tau) aggregation, as well as reactive oxygen species (ROS) generation, neuroinflammation, and oxidative stress. Therefore, there is a huge unmet need to develop diagnostic agents that can detect at an earlier stage the formation of oligomeric aggregates of the various amyloid proteins involved in proteinopathies (such as Aβ and p-tau in AD, and α-synuclein in PD), as well as target other hallmarks of these disorders such as neuroinflammation and oxidative stress. Herein, we plan to employ a fundamental chemical approach to generate novel blood-brain barrier permeable multifunctional and dual PET/MRI imaging agents and evaluate in vivo their ability as diagnostic agents for AD and ADRD. In these studies, we will employ novel organic and inorganic chemical design principles and synthetic approaches, along with the detailed characterization of the developed bioinorganic systems for imaging/diagnostic applications. Progress in all presented research directions will lead to the development and optimization of novel diagnostic agents for advancing human health.