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.

项目总结 选择性调节γ分泌酶活性已成为阿尔茨海默病的一种治疗策略 (Ad)因为它控制了致病Aβ42种的水平。我们已经开发出一类γ-分泌酶 调节器(GSM)，一组小分子，通过以下方式专门调节APP的γ-分泌酶处理 结合γ-分泌酶的PS1组分，从而优先降低Aβ42的水平而不是Aβ40，同时增加 较短的Aβ种的水平。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，我们开发了一个新的系列 在降低细胞和细胞内Aβ42水平方面显示出前所未有的有效性的哒嗪类SGSM 基于动物的研究，具有理想的类药物特性，因此使它们在AD临床上表现突出 候选人。我们已经报告了这一新类别中的领先临床候选对象，SGSM-15606(Aβ42的IC50值 =7 nm)。这种分子和相关类似物是根据一种预研新药的计划开发出来的 (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-分泌酶参与阿尔茨海默病的分子生物学研究在非侵入性的 成像技术，正电子发射断层扫描(PET)是提供基本问题答案的理想工具 关于活着的人脑中的γ分泌酶的问题。此外，它还提供了一种既可以研究γ- 非侵入性地分泌机制，促进药物开发。在过去的十年中，有 几种潜在的AD疾病修改疗法进入临床试验。然而，AD疗法 临床试验的失败率很高，部分原因是入选患者的多样性。在AD中 在试验中，患者通常被招募到广泛的诊断类别下，这通常与 不确定的或否定的试验结果。为了解决这个问题，临床研究最近开始应用 PET成像选择更同质的患者组。例如，将聚酯配体用于β 斑块和神经原纤维tau缠结在临床试验中变得更加常见，并使更好的清晰度成为可能 临床试验的最佳患者组。 在我们的计划中，我们将开发新的基于gsm的γ分泌酶正电子发射体层摄影成像探针作为 通过测量体内靶点占有率来帮助GSM临床特征的翻译工具。结果是 我们的研究将促进我们的SGSM用于AD干预的潜在临床试验。此外，使用 我们的正电子发射计算机断层扫描探针的问世，首次对AD患者的γ-分泌酶的性质进行了定量， 这最终可能提供对AD病因学的更全面的理解。