[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 发现作为伴侣诊断和/或有助于理解异常的人类放射性示踪剂 认知障碍的基础的生物学过程，例如阿尔茨海默氏病（AD）和其他大脑 疾病是与与实施相关的关键里程碑的高转化优先级的领域 国家计划解决阿尔茨海默氏症和相关痴呆症的计划以及PAR-20-038的特定要求。 我们的研究提出了对正电子发射的放射性药物的发现和评估 层析成像（PET）成ch的成像，AD中的新兴靶标。伴侣，长寿命的寡聚 蛋白质脚手架平台是AD发病机理的最早介体之一。它们对 蛋白质的相互作用对神经元功能重要的相互作用，例如突触可塑性，细胞对细胞通信， 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 - 蛋白质相互作用网络中的全蛋白质组缺陷以及细胞和脑网络功能障碍 和认知能力下降。我们发现了伴随药物（例如PU-AD）和伴侣诊断（例如。 [124i] -pu-ad PET）并将其转换为诊所。为了图像表面伴侣，我们发现[124i] -pu-ad，a [124i] - 标记的伴随探针。在一项试验可行性临床研究中，[124i] -pu-ad提供了原理证明 PET的患者中的表周期可进行想象和量化。在临床前模型中，它证明了 与疾病相关的区域和年龄依赖性的方式形成了AD的附生伴侣。 下一步是使伴随成像成像探针可用于广泛的临床用途。我们假设更换 具有18F的124i标签将显着提高灵敏度，空间和时间图像质量，降低辐射 负担和成像时间，提高生产成本和可用性，从而提高了临床适用性 探针。我们在这里提出了一项计划，以发现18F Epichaperome宠物成像剂重点 在诸如综合，识别铅候选者，示踪剂表征，安全性，给药，临床前等步骤中 对拟议的未来探索性研究新药应用的验证和辅助研究。我们 组装一个具有成功合作历史的多学科团队（> 40篇论文，> 20个宠物示踪剂 诊所）并设计了3个特定目的旨在实现我们的目标：目标1。确定含有F的Epichoperome探针 具有良好的亲和力，选择性和BBB渗透性；目标2。研究探测的特异性和敏感性 在检测AD小鼠模型中的表伴介导的功能障碍时；和目标3。执行辅助研究 对于拟议的探索性研究新药应用。 这项工作的结果是用作精确医学工具的新型宠物探针，以形象在体内图像早期分子 这两个研究领域 高转化优先级。

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

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

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

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