[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.

摘要 发现可作为辅助诊断和/或帮助理解异常的人类放射性示踪剂 认知障碍的生物过程，如阿尔茨海默病(AD)和其他大脑 障碍是一个高度优先翻译的领域，与实施 解决阿尔茨海默氏症和相关痴呆症的国家计划和PAR-20-038的具体要求。 我们的研究建议发现和评价一种正电子发射的放射性药物。 阿尔茨海默病的新靶点--上壳体的断层扫描(PET)成像。长寿寡聚体--上胚层 蛋白质支架平台是AD发病机制中最早的介质之一。它们负面影响了 对神经元功能很重要的蛋白质的相互作用，如突触可塑性，细胞间通讯， 蛋白质翻译、细胞周期重新进入、轴突引导、代谢过程和炎症，导致 蛋白质相互作用网络中的蛋白质组缺陷，进而导致细胞和脑网络功能障碍 和认知能力下降。我们发现了两种外种皮药物(例如。PU-AD)和配套诊断(例如 [124I]-PU-AD PET)，并将其翻译到临床。为了对表壳体进行成像，我们发现了[124I]-PU-AD，a[124I]- 标记的外种皮探针。在一项试验性可行性临床研究中，[124I]-PU-AD提供了原则证明 通过正电子发射计算机断层扫描，患者的上壳体是可成像和可量化的。在临床前模型中，它证明了 上壳体在AD中以与疾病相关的区域和年龄相关的方式形成。 下一步是使外种皮成像探针在临床上得到广泛应用。我们假定更换 带有18F的124I标记将显著提高灵敏度、空间和时间图像质量，减少辐射 负担和成像时间，提高了生产成本和可用性，从而增加了临床适用性 探测器。我们在这里提出了一个发现18F表壳体PET显像剂的计划，重点是 关于合成、候选铅的鉴定、示踪剂表征、安全性、剂量、临床前 未来拟议的探索性调查新药应用的验证和使能IND的研究。我们 组建一个有成功合作历史的多学科团队(&gt；40篇论文，&gt；20个PET示踪剂，在 临床)，并设计了3个具体的目标来实现我们的目标：目标1.鉴定含F的外壳体探针 具有良好的亲和力、选择性和血脑屏障通透性；目的2.考察探针的特异性和敏感性 在AD小鼠模型中检测外种皮介导的功能障碍；以及目标3.进行启用IND的研究 一项拟议的探索性调查新药申请。 这项工作的成果是用作精确医学工具的新型PET探针，用于体内早期分子的成像 脑功能障碍和作为外壳体靶向治疗的辅助诊断，这两个研究领域 具有很高的翻译优先级。

项目成果

Pareto-Optimized Non-Negative Matrix Factorization Approach to the Cleaning of Alaryngeal Speech Signals.

• DOI: 10.3390/cancers15143644
• 发表时间: 2023-07-16
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Maskeliunas, Rytis;Damasevicius, Robertas;Kulikajevas, Audrius;Pribuisis, Kipras;Ulozaite-Staniene, Nora;Uloza, Virgilijus
• 通讯作者: Uloza, Virgilijus

Accuracy Analysis of the Multiparametric Acoustic Voice Indices, the VWI, AVQI, ABI, and DSI Measures, in Differentiating between Normal and Dysphonic Voices.

• DOI: 10.3390/jcm13010099
• 发表时间: 2023-12-23
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Uloza V;Pribuišis K;Ulozaite-Staniene N;Petrauskas T;Damaševičius R;Maskeliūnas R
• 通讯作者: Maskeliūnas R

Assessing the Occurrence and Distribution of Microplastics in Surface Freshwater and Wastewaters of Latvia and Lithuania.

• DOI: 10.3390/toxics11040292
• 发表时间: 2023-03-23
• 期刊: Toxics
• 影响因子: 4.6
• 作者: Pashaei R;Sabaliauskaitė V;Suzdalev S;Balčiūnas A;Putna-Nimane I;Rees RM;Dzingelevičienė R
• 通讯作者: Dzingelevičienė R

Development of a Low-Frequency Piezoelectric Ultrasonic Transducer for Biological Tissue Sonication.

• DOI: 10.3390/s23073608
• 发表时间: 2023-03-30
• 期刊: Sensors (Basel, Switzerland)
• 作者: Ostasevicius V;Jurenas V;Mikuckyte S;Vezys J;Stankevicius E;Bubulis A;Venslauskas M;Kizauskiene L
• 通讯作者: Kizauskiene L

Reliability of Universal-Platform-Based Voice Screen Application in AVQI Measurements Captured with Different Smartphones.

基于通用平台的语音屏幕应用在不同智能手机 AVQI 测量中的可靠性。

• DOI: 10.3390/jcm12124119
• 发表时间: 2023-06-18
• 期刊: JOURNAL OF CLINICAL MEDICINE
• 影响因子: 3.9
• 作者: Uloza, Virgilijus;Ulozaite-Staniene, Nora;Petrauskas, Tadas;Pribuisis, Kipras;Blazauskas, Tomas;Damasevicius, Robertas;Maskeliunas, Rytis
• 通讯作者: Maskeliunas, Rytis