[18F]-PU-AD epichaperome PET imaging probe

[18F]-PU-AD外表面组PET成像探针

• 批准号: 10445594
• 负责人: GABRIELA CHIOSIS
• 金额: $ 358.98万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445594
• 关键词: Address; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Amyloid beta-Protein; Area; Autopsy; Autoradiography; Binding; Biological Assay; Biological Markers; Biological Process; Brain; Brain Diseases; Brain region; Cell Communication; Cell Cycle; Cells; Central Nervous System Diseases; Chemistry; Clinic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cognition Disorders; Collaborations; Complex; Data; Defect; Detection; Diagnostic; Disadvantaged; Disease; Disease Progression; Dose; Evaluation; Functional Imaging; Functional disorder; Future; Generations; Goals; Half-Life; Human; Image; Impaired cognition; In Vitro; Induced pluripotent stem cell derived neurons; Inflammation; Investigation; Investigational New Drug Application; Isotopes; Label; Lead; Mediating; Mediator of activation protein; Metabolism; Methods; Modeling; Molecular; Monitor; Neurons; Outcome; Paper; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Positron-Emission Tomography; Pre-Clinical Model; Production; Property; Proteins; Proteome; Radiation; Radiolabeled; Radiopharmaceuticals; Recording of previous events; Reproducibility; Research; Rodent; Safety; Scaffolding Protein; Selection Criteria; Sensitivity and Specificity; Severities; Signal Transduction; Site; Specific qualifier value; Standardization; Structure; Symptoms; Synaptic plasticity; Therapeutic; Therapeutic Agents; Time; Tracer; Transgenic Mice; Translating; Translations; Treatment Efficacy; Validation; Work; Writing; age related; axon guidance; blood-brain barrier permeabilization; clinical application; companion diagnostics; cost; design; dosimetry; drug candidate; expectation; human disease; imaging agent; imaging probe; improved; in vivo; in vivo imaging; lead candidate; mouse model; multidisciplinary; network dysfunction; non-invasive imaging; novel; novel therapeutics; phase 2 study; pre-clinical; pre-clinical research; precision medicine; preclinical safety; protein protein interaction; radioligand; radiotracer; scaffold; spatiotemporal; success; targeted imaging; targeted treatment; tau Proteins; tool; uptake

ABSTRACT Discovery of human radiotracers that serve as companion diagnostics and/or aid in understanding abnormal biological processes that underlie cognitive disorders, such as Alzheimer's disease (AD) and other brain disorders is an area of high translational priority towards key milestones tied to the implementation of the National Plan to Address Alzheimer's and Related Dementias and a specific requirement of PAR-20-038. Our study proposes the discovery and evaluation of a radiopharmaceutical agent for the positron emission tomography (PET) imaging of epichaperomes, emerging targets in AD. Epichaperomes, long-lived oligomeric protein scaffolding platforms, are among the earliest mediators of AD pathogenesis. They negatively impact the interactions of proteins important for neuronal function, such as synaptic plasticity, cell-to-cell communication, protein translation, cell cycle re-entry, axon guidance, metabolic processes and inflammation, leading to proteome-wide defects in protein-protein interaction networks, and in turn cell- and brain-network dysfunction and cognitive decline. We discovered both epichaperome drugs (eg. PU-AD) and companion diagnostics (eg. [124I]-PU-AD PET) and translated them to clinic. To image epichaperomes, we discovered [124I]-PU-AD, a [124I]- labeled epichaperome probe. In a pilot feasibility clinical study, [124I]-PU-AD provided proof-of-principle that epichaperomes are imageable and quantifiable in patients by PET. In preclinical models, it demonstrated that epichaperomes form in AD in a disease-relevant region- and age-dependent manner. The next step is to make epichaperome imaging probes practical for widespread clinical use. We posit replacing the 124I label with 18F will significantly improve sensitivity, spatial and temporal image quality, reduce radiation burden and imaging times, improve production costs and availability, thus increasing the clinical applicability of the probe. We here propose a plan for the discovery of the 18F epichaperome PET imaging agent with emphasis on steps such as synthesis, identification of lead candidates, tracer characterization, safety, dosing, preclinical validation and IND-enabling studies for a proposed future Exploratory Investigational New Drug Application. We assemble a multidisciplinary team with a history of successful collaborations (>40 papers, >20 PET tracers in clinic) and designed 3 Specific Aims to accomplish our goal: Aim 1. Identify F-containing epichaperome probes with favorable affinity, selectivity and BBB permeability; Aim 2. Investigate the probe's specificity and sensitivity in detecting epichaperome-mediated dysfunction in AD mouse models; and Aim 3. Perform IND-enabling studies for a proposed Exploratory Investigational New Drug Application. Outcomes of this work are novel PET probes for use as precision medicine tools to image in vivo early molecular dysfunction in the brain and as companion diagnostics for epichaperome targeted therapies, both research areas of high translational priority.

抽象的 发现可作为伴随诊断和/或帮助了解异常的人体放射性示踪剂 认知障碍（例如阿尔茨海默病 (AD) 和其他大脑疾病）背后的生物过程 疾病是实现与实施相关的关键里程碑的高度转化优先领域 解决阿尔茨海默病和相关痴呆症的国家计划以及 PAR-20-038 的具体要求。 我们的研究提出了用于正电子发射的放射性药剂的发现和评估 表层体的断层扫描 (PET) 成像，AD 中的新兴目标。 Epichaperomes，长寿命寡聚体 蛋白质支架平台是 AD 发病机制的最早介质之一。它们对 对神经元功能很重要的蛋白质相互作用，例如突触可塑性、细胞间通讯、 蛋白质翻译、细胞周期重入、轴突引导、代谢过程和炎症，导致 蛋白质-蛋白质相互作用网络中蛋白质组范围的缺陷，进而导致细胞和大脑网络功能障碍 和认知能力下降。我们发现了表层组药物（例如 PU-AD）和伴随诊断（例如 [124I]-PU-AD PET）并将其转化为临床。为了对表壳组进行成像，我们发现了[124I]-PU-AD，一种[124I]- 标记的外表面组探针。在一项试点可行性临床研究中，[124I]-PU-AD 提供了原理证明： 通过 PET 可对患者的表层体进行成像和定量。在临床前模型中，它证明了 AD 中表层体的形成与疾病相关的区域和年龄相关。 下一步是使外表面组成像探针能够广泛应用于临床。我们假设替换 124I标签配合18F将显着提高灵敏度、空间和时间图像质量，减少辐射 负担和成像时间，提高生产成本和可用性，从而提高临床适用性 探头。我们在此重点提出18F表层PET显像剂的发现计划 合成、先导候选物的鉴定、示踪剂表征、安全性、剂量、临床前等步骤 拟议的未来探索性研究新药申请的验证和 IND 支持研究。我们 组建一支具有成功合作历史的多学科团队（> 40 篇论文，> 20 种 PET 示踪剂 诊所）并设计了 3 个具体目标来实现我们的目标： 目标 1. 识别含 F 的表层探针 具有良好的亲和力、选择性和BBB通透性；目标 2. 研究探针的特异性和灵敏度 检测 AD 小鼠模型中表层体介导的功能障碍；目标 3. 进行 IND 支持研究 拟议的探索性研究新药申请。 这项工作的成果是新型 PET 探针，可用作精密医学工具，对体内早期分子进行成像 大脑功能障碍和作为表层体靶向治疗的伴随诊断，这两个研究领域 具有高翻译优先级。

项目成果

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• 影响因子: 4.6
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