Development of Emergent PET Tracers in Frontotemporal Lobar Degeneration

额颞叶变性紧急 PET 示踪剂的开发

基本信息

批准号：
10429831
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
项目类别：
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/10429831
关键词：
Advanced Development Affinity Aging Alzheimer&apos s Disease Alzheimer&apos 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 (Brain)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 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 corticobasal degeneration corticobasal syndrome diagnostic criteria disorder control drug development early onset experience hyperphosphorylated tau improved in vivo in vivo imaging instructor meetings mild cognitive impairment molecular pathology mutation carrier neuroimaging neuroimaging marker neuropathology novel pharmacokinetic model precision medicine preclinical development programs protein TDP-43 putamen radiotracer recruit research and development research clinical testing skills tau Proteins tau aggregation treatment response uptake

项目摘要

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.

项目摘要/摘要这是针对行为的K23职业发展奖申请神经科医生和临床讲师，他是大学的初级调查员加利福尼亚，旧金山（UCSF）记忆和老化中心（MAC）。他的长期目标是成为一个临床医生科学家将领导一项独立研究计划，以推动前临床前用于诊断和监测神经退行性疾病的新型宠物示踪剂的开发/翻译与额颞叶变性（FTLD）病理相关。通过K23和最佳培训 Mac的环境和资源，Soleimani-Meigooni博士旨在实现这些培训目标：1。精通PET图像采集的药代动力学放射性示例建模和优化。 2 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。为了获得临床研究操作的技能，研究道德和授予技巧。 6。将他的K23培训和调查结果实施到R01中，这将使他能够成为参与新型宠物示踪剂的临床前开发/翻译的独立研究者 ftld。为了实现这些培训目标，Soleimani-Meigooni博士召集了一个世界一流的指导团队包括主要导师，吉尔·拉比诺维奇博士，行为神经科医生，宠物神经影像学的领导者神经退行性疾病；联合官员，行为神经科医生兼技术专家威廉·贾格斯特（William Jagust）博士 PET成像的各个方面，包括放射性示意剂的发育和药代动力学建模；联合官员，Lea博士 Grinberg，神经病理学家，UCSF神经退行性疾病脑库的共同领导者，专家 FTLD和定量神经病理学措施；合作者Suzanne Baker博士，技术科学家宠物成像方面的专业知识；而且，合作者伊莎贝尔·伊莱恩·艾伦（Isabel Elaine Allen）博士是专业的生物统计学家。该项目将评估/验证新的宠物示踪剂，以帮助诊断和监测FTLD。候选人宠物示踪剂包括一种与非阿尔茨海默氏症tau蛋白结合的新型配体，[18f] pi-2620和另一种配体结合突触[18F] Synvest-1。需要进一步评估以确定[18F] PI-2620是否可以用Tau病理学（FTLD-TAU）与FTLD区分FTLD，并使用TDP-43病理学（FTLD-TDP）区分FTLD，如果 [18F] Synvest-1是FTLD中突触丧失和疾病状态的敏感标志。在这个项目中，两个示踪剂将通过比较FTLD-TAU患者的示踪剂保留模式与FTLD-TDP进行评估/验证和其他神经退行性疾病（AIM 1）；将保留区域示踪剂与临床措施相关联结构性大脑MRI变化（皮质厚度或皮层下体积的丧失）（AIM 2）；和表演定量宠物病理学相关性（AIM 3）。该项目提供了可以支持的关键数据这些放射性示例的翻译临床使用和应用为临床试验生物标志物。