Development of Emergent PET Tracers in Frontotemporal Lobar Degeneration

额颞叶变性紧急 PET 示踪剂的开发

• 批准号: 10676768
• 负责人: David Nima Soleimani-Meigooni
• 金额: $ 19.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676768
• 关键词: Acceleration; Advanced Development; Affinity; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Area; Argyrophilic Grain Disease; Autopsy; Basal Ganglia; Behavioral; Binding; Biological Markers; Biometry; Brain; Brain Diseases; C9ORF72; California; Categories; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cognitive; Data; Data Collection; Dementia; Development; Diagnosis; Diagnostic; Differential Diagnosis; Disease; Disease Progression; Drug Kinetics; Environment; Evaluation; Fluorine; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Genetic; Globus Pallidus; Goals; Grant; Hippocampus; Immunoassay; Immunohistochemistry; In Vitro; Individual; Infrastructure; Integral Membrane Protein; K-Series Research Career Programs; Label; Lead; Learning; Ligand Binding; Ligands; Magnetic Resonance Imaging; Measures; Medial; Memory; Mentors; Mentorship; Methods; Modeling; Monitor; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurologist; Operations Research; Orphan Drugs; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patient Recruitments; Patients; Pattern; Phenotype; Pick Disease of the Brain; Positron-Emission Tomography; Presynaptic Terminals; Primary Progressive Aphasia; Progressive Supranuclear Palsy; Protein Isoforms; Proteins; Qualifying; Recombinants; Research; Research Design; Research Ethics; Research Personnel; Resources; San Francisco; Scientist; Semantics; Sensitivity and Specificity; Site; Standardization; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; Synaptic Vesicles; Synaptophysin; Syndrome; Tauopathies; Technical Expertise; Techniques; Temporal Lobe; Thick; Tracer; Training; Translations; Universities; Validation; Variant; analog; brain magnetic resonance imaging; career; career development; clinical diagnosis; clinical diagnostics; comparison control; corticobasal degeneration; corticobasal syndrome; diagnostic criteria; disorder control; drug development; early onset; experience; fluorodeoxyglucose positron emission tomography; hyperphosphorylated tau; improved; in vivo; in vivo imaging; instructor; meetings; mild cognitive impairment; molecular pathology; mutation carrier; neocortical; neuroimaging; neuroimaging marker; neuropathology; novel; pharmacokinetic model; precision medicine; preclinical development; programs; protein TDP-43; putamen; radiotracer; recruit; research clinical testing; skills; tau Proteins; tau aggregation; treatment response; uptake

PROJECT SUMMARY/ABSTRACT This is a K23 career development award application for Dr. David Soleimani-Meigooni, a behavioral neurologist and Clinical Instructor who is establishing himself as a junior investigator at the University of California, San Francisco (UCSF) Memory and Aging Center (MAC). His long-term goal is to become a clinician-scientist who will lead an independent research program to advance the pre-clinical development/translation of novel PET tracers for diagnosis and monitoring of neurodegenerative diseases associated with frontotemporal lobar degeneration (FTLD) pathology. Through the K23 and the optimal training environment and resources of the MAC, Dr. Soleimani-Meigooni aims to achieve these training goals: 1. To become proficient in pharmacokinetic radiotracer modeling and optimization of PET image acquisition. 2. To become proficient in quantitative PET analyses. 3. To learn quantitative neuropathology techniques. 4. To gain advanced skills in study design and biostatistics. 5. To gain skills in clinical research operations, research ethics, and grantsmanship. 6. To implement his K23 training and findings into an R01 that will allow him to become an independent investigator involved in pre-clinical development/translation of novel PET tracers for FTLD. To achieve these training goals, Dr. Soleimani-Meigooni has assembled a world-class mentorship team including primary mentor, Dr. Gil Rabinovici, a behavioral neurologist and leader in PET neuroimaging of neurodegenerative diseases; co-mentor, Dr. William Jagust, a behavioral neurologist and expert in technical aspects of PET imaging, including radiotracer development and pharmacokinetic modeling; co-mentor, Dr. Lea Grinberg, a neuropathologist, co-leader of the UCSF Neurodegenerative Disease Brain Bank, and expert on FTLD and quantitative neuropathological measures; collaborator, Dr. Suzanne Baker, a scientist with technical expertise in PET imaging; and, collaborator, Dr. Isabel Elaine Allen, an expert biostatistician. This project will evaluate/validate new PET tracers to aid in diagnosis and monitoring of FTLD. Candidate PET tracers include a novel ligand that binds to non-Alzheimer tau proteins, [18F]PI-2620, and another ligand that binds to synapses, [18F]SynVesT-1. Further evaluation is needed to determine if [18F]PI-2620 can distinguish FTLD with tau pathology (FTLD-tau) from FTLD with TDP-43 pathology (FTLD-TDP), and if [18F]SynVesT-1 is a sensitive marker of synapse loss and disease state in FTLD. In this project, both tracers will be evaluated/validated by comparing patterns of tracer retention in patients with FTLD-tau to FTLD-TDP and other neurodegenerative diseases (Aim 1); correlating regional tracer retention to clinical measures and structural brain MRI changes (loss of cortical thickness or subcortical volume) (Aim 2); and performing quantitative PET-to-pathology correlations (Aim 3). This project provides critical data that could support the translation of these radiotracers for clinical use and application as clinical trial biomarkers.

项目概要/摘要 这是 David Soleimani-Meigooni 博士的 K23 职业发展奖申请，他是一名行为学专家 神经学家和临床讲师，正在大学担任初级研究员 加利福尼亚州旧金山 (UCSF) 记忆与衰老中心 (MAC)。他的长期目标是成为一名 临床医生科学家将领导一个独立的研究项目以推进临床前研究 开发/翻译用于诊断和监测神经退行性疾病的新型 PET 示踪剂 与额颞叶变性（FTLD）病理学相关。通过K23和优化训练 Soleimani-Meigooni 博士旨在利用 MAC 的环境和资源来实现以下培训目标： 1. 精通药代动力学放射性示踪剂建模和 PET 图像采集优化。 2. 到 精通定量 PET 分析。 3.学习定量神经病理学技术。 4. 获得 研究设计和生物统计学的高级技能。 5. 获得临床研究操作、研究的技能 道德和捐赠精神。 6. 将他的 K23 培训和发现应用到 R01 中，这将使他能够 成为一名独立研究者，参与新型 PET 示踪剂的临床前开发/翻译 FTLD。为了实现这些培训目标，Soleimani-Meigooni 博士组建了一支世界一流的导师团队 其中包括主要导师 Gil Rabinovici 博士，他是一位行为神经学家，也是 PET 神经影像领域的领导者 神经退行性疾病；共同导师 William Jagust 博士，行为神经学家和技术专家 PET 成像方面，包括放射性示踪剂开发和药代动力学模型；联合导师，Lea 博士 格林伯格（Grinberg），神经病理学家，加州大学旧金山分校神经退行性疾病脑库联合负责人， FTLD 和定量神经病理学测量；合作者苏珊·贝克博士 (Dr. Suzanne Baker)，一位拥有技术知识的科学家 PET 成像专业知识；合作者是生物统计学家伊莎贝尔·伊莱恩·艾伦 (Isabel Elaine Allen) 博士。 该项目将评估/验证新的 PET 示踪剂，以帮助诊断和监测 FTLD。候选人 PET 示踪剂包括一种与非阿尔茨海默 tau 蛋白结合的新型配体 [18F]PI-2620 和另一种配体 与突触结合，[18F]SynVesT-1。需要进一步评估以确定 [18F]PI-2620 是否可以 区分具有 tau 病理学的 FTLD (FTLD-tau) 和具有 TDP-43 病理学的 FTLD (FTLD-TDP)，并且如果 [18F]SynVesT-1 是 FTLD 突触丢失和疾病状态的敏感标记。在这个项目中，两个示踪剂 将通过比较 FTLD-tau 患者与 FTLD-TDP 患者示踪剂保留模式来评估/验证 和其他神经退行性疾病（目标 1）；将区域示踪剂保留与临床测量相关联 大脑结构 MRI 变化（皮质厚度或皮质下体积损失）（目标 2）；并表演 定量 PET 与病理学相关性（目标 3）。该项目提供了可以支持的关键数据 将这些放射性示踪剂转化为临床用途并作为临床试验生物标志物应用。

项目成果

Tau PET Visual Reads: Research and Clinical Applications and Future Directions.

Tau PET 视觉读物：研究和临床应用以及未来方向。

• 发表时间: 2023-05
• 作者: Soleimani;Rabinovici, Gil D
• 通讯作者: Rabinovici, Gil D