Blood-Brain Barrier Permeable Multimodal Imaging Agents for Neurodegenerative Diseases

用于神经退行性疾病的血脑屏障渗透性多模态成像剂

• 批准号: 10740351
• 负责人: LIVIU M. MIRICA
• 金额: $ 178.37万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740351
• 关键词: Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Amyloid deposition; Amyotrophic Lateral Sclerosis; Anti-Inflammatory Agents; Antioxidants; Autopsy; Binding; Biology; Brain; Cause of Death; Chelating Agents; Chemicals; Chemistry; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Exhibits; Generations; Health; Human; Image; Inorganic Chemicals; Ions; Kinetics; Lewy Body Dementia; Ligands; Magnetic Resonance Imaging; Mission; Multimodal Imaging; Mus; Neurodegenerative Disorders; Organic Chemicals; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Peptides; Persons; Play; Positron-Emission Tomography; Proteins; Public Health; Reactive Oxygen Species; Reporting; Research; Seat Belts; Senile Plaques; Series; Testing; Thermodynamics; Transgenic Mice; United States; United States National Institutes of Health; Validation; Work; abeta oligomer; alpha synuclein; blood-brain barrier crossing; blood-brain barrier permeabilization; design; diagnostic tool; frontotemporal degeneration; imaging agent; imaging approach; imaging system; improved; in vivo; mouse model; neuroinflammation; neuropathology; new therapeutic target; novel; novel diagnostics; optical imaging; targeted agent; tau-1

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.

项目摘要 /摘要 Petides和蛋白质的聚集在许多毁灭性神经退行性疾病中起关键作用， 包括阿尔茨海默氏病（AD）和其他与AD相关的痴呆症（ADRD），例如Lewy身体痴呆症（LBD） 和额颞变性（FTD）以及帕金森氏病（PD）和肌萎缩性侧面硬化症 （ALS）。在这些淀粉样蛋白疾病或蛋白质病中，阿尔茨海默氏病（AD）是最常见的 神经退行性疾病和美国第六大死亡原因。大约有600万人 目前在美国被诊断为广告，预计到2050年将达到1400万。 没有针对AD的疾病改良治疗及其诊断的精度高，需要详细的验尸 检查大脑。虽然AD的主要神经病理标志是淀粉样斑的沉积 完成淀粉样β（Aβ）胡椒粉，新的治疗靶标还包括磷酸化的tau（p-tau） 聚集以及活性氧（ROS）产生，神经炎症和氧化应激。 因此，有巨大的未满足需要开发可以在早期阶段检测的诊断剂 参与蛋白质的各种淀粉样蛋白的寡聚聚集体的形成（例如Aβ和 AD中的P-TAU，PD中的α-核蛋白），以及这些疾病的其他标志，例如 神经炎症和氧化应激。在此，我们计划采用一种基本化学方法 产生新型的血脑屏障可渗透多功能和双PET/MRI成像剂，并在 Vivo作为AD和ADRD的诊断剂的能力。在这些研究中，我们将采用新颖的有机和 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。所有提出的研究进展 方向将导致新型诊断剂的发展和优化，以推动人类健康。