Molecular imaging of PS1/gamma-secretase and analysis of Alzheimer's disease.

PS1/γ-分泌酶的分子成像和阿尔茨海默病的分析。

• 批准号: 9901420
• 负责人: Changning Wang
• 金额: $ 20.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901420
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Binding; Binding Proteins; Biological Assay; Brain; Brain imaging; Categories; Cells; Clinical; Clinical Research; Clinical Trials; Clinical Trials Cooperative Group; Cognitive deficits; Data; Dementia; Development; Diagnostic; Disease; Dose; Drug Kinetics; Enrollment; Etiology; Event; FDA approved; Failure; Functional disorder; Generations; Goals; Grant; Human; Image; Imaging Device; Imaging Techniques; Intervention; Intervention Trial; Investigational Drugs; Investigational New Drug Application; Kinetics; Lead; Ligands; Measures; Medicine; Metabolism; Methods; Mus; Mutation; Nature; Neurodegenerative Disorders; Outcome; Parents; Pathogenicity; Pathologic; Patient Selection; Patients; Peptides; Performance; Pharmaceutical Preparations; Pharmacology; Phase Ia Trial; Phenotype; Plasma; Play; Positron-Emission Tomography; Program Development; Property; Pyridazines; Radio; Radiolabeled; Reporting; Rodent; Role; Senile Plaques; Series; Site; Solubility; Specificity; Structure; Therapeutic; Time; Tissues; Tracer; Transgenic Mice; Translating; United States National Institutes of Health; advanced disease; analog; aqueous; base; beta secretase; clinical candidate; density; design; dosimetry; drug development; effective therapy; gamma secretase; imaging agent; imaging probe; improved; in vivo; in vivo imaging; interest; kinetic model; molecular imaging; non-invasive imaging; nonhuman primate; notch protein; novel; programs; radiochemical; radiotracer; recruit; response; small molecule; tau aggregation; tool; uptake

PROJECT SUMMARY Selectively modulating γ-secretase activity has emerged as a therapeutic strategy for Alzheimer's disease (AD) because it controls the levels of pathogenic Aβ42 species. We have developed a class of γ-secretase modulators (GSMs), a group of small molecules that specifically modulate γ-secretase processing of APP by binding γ-secretase's PS1 components and thus preferentially lower Aβ42 levels over Aβ40, while increasing the levels of shorter Aβ species. Our GSMs do not affect the cleavage of other γ-secretase substrates, e.g. Notch. Our GSM program evolved several generations of development. Recently, we have developed a novel series of pyridazine class SGSMs which displayed unprecedented level of efficacy in lowering Aβ42 levels in cell and animal-based studies, with desirable drug-like properties, thus making them outstanding AD clinical candidates. We have reported a lead clinical candidate within this new class, SGSM-15606 (IC50 of Aβ42 =7nM). This molecule and related analogs have been developed with a plan for a pre-Investigational New Drug (IND) inquiry toward an AD intervention trial. Our GSM program has provided a unique opportunity to characterize the in vivo selectivity, distribution and involvement of γ-secretase in the pathophysiology of AD by molecular imaging. Among the non-invasive imaging techniques, positron emission tomography (PET) is an ideal tool to deliver answers to fundamental questions about γ-secretase in the living human brain. Furthermore, it provides a method to both investigate γ- secretase mechanisms non-invasively and improve drug development. During the past decade, there are several potential disease-modifying therapies for AD advanced to clinical trials. However, the AD therapeutics have a high failure rate for clinical trials partly due to the heterogeneous nature of enrolled patients. In AD trials, patients have been typically recruited under broad diagnostic categories, which is usually related to inconclusive or negative trial outcomes. To address this issue, clinical studies have recently started to apply PET imaging to choose more homogeneous patient groups. For example, the use of PET ligands for Aβ plaques and neurofibrillary tau tangles have become more routine in clinical trials and enabling better definition of optimal patient groups for clinical trials. In our proposal, we will develop new GSM-based γ-secretase PET imaging probes to serve as a translational tool to help clinical characterization of GSMs by measuring in vivo target occupancy. The results of our studies should facilitate a potential clinical trial of our SGSMs for AD intervention. Additionally, with the availability of our PET probe, the properties of γ-secretase in AD patients could be quantified for the first time, which may ultimately provide a more comprehensive understanding of AD etiology.

项目摘要 选择性调节γ-分泌酶活性已成为阿尔茨海默氏病的治疗策略 （AD）因为它控制着致病性Aβ42种的水平。我们已经开发了一类γ-分泌酶 调节剂（GSM），一组小分子，该分子特异性地调节了APP的γ-分泌酶处理 结合γ-分泌酶的PS1成分，因此优选地降低了Aβ40的Aβ42水平，同时增加了 较短的Aβ水平。我们的GSM不影响其他γ-分泌酶底物的裂解，例如缺口。 我们的GSM计划发展了几代发展。最近，我们开发了一个新颖的系列 吡啶嗪类SGSM的表现出前所未有的效率水平，以降低细胞的Aβ42水平 基于动物的研究，具有理想的药物样特性，因此使其成为出色的AD临床 候选人。我们报道了该新类别SGSM-15606（Aβ42的IC50）中的铅临床候选者 = 7nm）。该分子和相关的类似物是通过计划前新药的计划开发的 （IND）对AD干预试验进行查询。 我们的GSM计划提供了一个独特的机会来表征体内选择性，分布和 通过分子成像，γ-分泌酶参与AD的病理生理学。在非侵入性中 成像技术，极性发射断层扫描（PET）是提供基本答案的理想工具 关于活体大脑中γ-分泌酶的问题。此外，它提供了一种研究γ-的方法 泌尿酶机制非侵入性并改善药物开发。在过去的十年中，有 用于临床试验的几种潜在的疾病改良疗法。但是，广告疗法 临床试验的失败率很高，部分原因是入学患者的异质性质。在广告中 试验，通常在广泛的诊断类别下招募患者，这通常与 尚无定论或负面试验结果。为了解决这个问题，临床研究最近开始适用 宠物成像以选择更多同质患者群体。例如，将宠物配体用于Aβ 在临床试验中，斑块和神经原纤维tau缠结已成为常规的常规方法，并可以更好地定义 用于临床试验的最佳患者组。 在我们的建议中，我们将开发新的基于GSM的γ-分泌酶PET成像问题，以作为一个 通过测量体内目标占用率来帮助GSM的临床表征的翻译工具。结果 我们的研究应促进我们的SGSM进行AD干预的潜在临床试验。另外，与 我们的PET探针的可用性，可以首次定量AD患者中γ-分泌酶的特性， 最终可能会提供对AD病因的更全面的理解。