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病的治疗策略 (AD)因为它控制着致病性Aβ42的水平。我们开发了一类γ-分泌酶 调节剂（GSM），一组通过以下方式特异性调节APP的γ-分泌酶加工的小分子： 结合γ-分泌酶的PS1组分，从而优先降低Aβ42水平，而不是Aβ40，同时增加 较短Aβ物质的水平。我们的GSM不影响其他γ-分泌酶底物的切割，例如Notch。 我们的GSM计划经历了几代人的发展。最近，我们开发了一个新颖的系列 哒嗪类SGSM在降低细胞中Aβ42水平方面表现出前所未有的疗效水平， 基于动物的研究，具有理想的药物样特性，因此使其成为杰出的AD临床 候选人我们已经报道了这一新类别中的主要临床候选药物SGSM-15606（Aβ42的IC 50 =7nM）。该分子和相关类似物已被开发为预研究新药计划 (IND)对AD干预试验的调查。 我们的GSM计划提供了一个独特的机会来表征体内的选择性，分布和 γ-分泌酶参与AD病理生理的分子影像学研究在非侵入性 成像技术，正电子发射断层扫描（PET）是一个理想的工具，提供答案的基本 关于人脑中γ分泌酶的问题此外，它还提供了一种研究γ- 分泌酶机制的非侵入性和改善药物开发。在过去的十年里， 几种潜在的改善AD疾病的疗法已进入临床试验阶段。然而，AD治疗方法 临床试验的失败率很高，部分原因是招募患者的异质性。AD中 在临床试验中，患者通常是在广泛的诊断类别下招募的，这通常与 不确定或负面的试验结果。为了解决这个问题，最近开始进行临床研究， PET成像选择更同质的患者群体。例如，针对Aβ的PET配体的使用 斑块和神经元tau蛋白缠结在临床试验中变得更加常见， 临床试验的最佳患者群体。 在我们的提案中，我们将开发新的基于GSM的γ-分泌酶PET成像探针， 翻译工具，通过测量体内靶标占有率来帮助临床表征GSM。结果 我们的研究应该有助于我们的SGSM干预AD的潜在临床试验。此外，使用 我们的PET探针的可用性，AD患者中γ-分泌酶的性质可以首次定量， 这可能最终提供对AD病因学的更全面的理解。