Synthesis and Evaluation of an 18F Labeled SV2A Ligand as a Novel Biomarker for Alzheimers Disease

18F 标记的 SV2A 配体作为阿尔茨海默病新型生物标志物的合成和评估

• 批准号: 9386361
• 负责人: Zhengxin Cai
• 金额: $ 17.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386361
• 关键词: Affect; Affinity; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Animal Model; Autoradiography; Award; Benzene; Binding; Biological Assay; Biological Markers; Brain; Characteristics; Clinic; Clinical; Communities; Data; Data Analyses; Dementia; Development; Disease; Disease Progression; Drug Kinetics; Early Diagnosis; Early Intervention; Economic Burden; Emotional; Evaluation; Family; Fluorine; Fostering; Functional disorder; Goals; High Pressure Liquid Chromatography; Hippocampus (Brain); Image; Impaired cognition; In Vitro; Investigation; Kinetics; Label; Lead; Ligands; Measurement; Memory; Memory impairment; Mentors; Metabolism; Modeling; Monitor; Monkeys; Mus; Neurodegenerative Disorders; Paper; Parkinson Disease; Patients; Penetration; Play; Positron-Emission Tomography; Prefrontal Cortex; Preparation; Proteins; Publishing; Radiolabeled; Reaction; Research; Research Activity; Research Personnel; Research Project Grants; Rodent Model; Role; Senile Plaques; Series; Slice; Specificity; Surrogate Markers; Synapses; Synaptic Vesicles; Techniques; Testing; Time; Tracer; Training; Transgenic Organisms; Translating; Translations; United States; analog; base; brain tissue; clinical translation; density; design; disorder control; drug development; early detection biomarkers; effective therapy; human study; image processing; imaging agent; imaging modality; imaging probe; imaging study; in vivo; in vivo imaging; mild cognitive impairment; mouse model; nervous system disorder; neuroimaging; neurotransmission; nonhuman primate; novel; novel marker; pre-clinical; skills; symposium; trafficking; translational study; uptake

ABSTRACT The goal of this award is to foster the transition of the applicant to an independent investigator in the field of PET neuroimaging focusing on the development and translation of novel PET neuroimaging probes for early detection of Alzheimer’s disease (AD) to clinics. The applicant is redirecting his research focus from oncological PET imaging to PET neuroimaging. And the new direction is significantly different from the applicant’s former training, not only in pathophysiology, but also in approaches to image acquisition, and especially data analysis (image processing, kinetic modeling), characteristics of the tracers (BBB penetration, pharmacokinetics, metabolism), and animal models for translational studies. The training plan includes focused coursework, seminars and conferences, interaction with mentors from fields of PET neuroimaging probe development, tracer kinetic modeling, anti-AD drug development, and clinical AD research. Through the proposed study, the applicant will acquire new techniques, i.e., ex vivo autoradiography, image processing, and kinetic modeling. The applicant will also acquire new skills such as preparation for IND application, which is required for translating the imaging agent to the clinic. The objective of the proposed research activities is to develop an 18F-labeled PET imaging probe for early detection of AD. The proposed research project is based on pilot data obtained using [11C]UCB-J, which demonstrated both the feasibility, and clinical potential, of imaging SV2A as a biomarker for preclinical or prodromal AD. To overcome the limitations of [11C]UCB-J, an 18F-labeled analog was proposed to be developed for the clinical translation. The specific aims of the proposal are: 1) To synthesize and evaluate enantiopure UCB-J analogs through in vitro homogenate binding assays; 2) To evaluate in nonhuman primates the in vivo pharmacokinetic and metabolism profiles of the [18F]UCB-J analogs advanced from Aim 1; 3) To use SV2A PET imaging to monitor the pre-dementia AD progression in a transgenic rodent model of AD through longitudinal multi-tracer PET imaging and ex vivo autoradiography. Successful completion of this project will yield a PET tracer ready to be translated to clinics for testing as a biomarker for early detection of AD.

抽象的 该奖项的目的是促进申请人的过渡到该领域的独立调查员 PET神经影像集中在早期的新型PET神经影像问题的发展和翻译上 对诊所的阿尔茨海默氏病（AD）的检测。申请人正在将他的研究重点转移到 肿瘤宠物成像宠物神经影像。新方向与 申请人的以前培训不仅在病理生理学方面，而且在图像获取的方法中以及 特别是数据分析（图像处理，动力学建模），示踪剂的特征（BBB穿透， 用于翻译研究的药代动力学，代谢）和动物模型。培训计划包括专注 课程工作，半手和会议，与宠物神经影像领域的互动证明 开发，示踪动力学建模，抗AD药物开发和临床AD研究。通过 拟议的研究，申请人将获取新技术，即体内自显影，图像处理， 和动力学建模。该应用程序还将获得新技能，例如为IND应用做准备， 将成像剂转换为诊所所必需。拟议的研究活动的目的是 开发一个标记为18F的PET成像探针，用于早期检测AD。拟议的研究项目基于 关于使用[11C] UCB-J获得的试验数据，这既证明了可行性和临床潜力 成像SV2A作为临床前或前驱AD的生物标志物。要克服[11C] UCB-J的局限性， 提议为临床翻译开发18F标记的类似物。提案的具体目的 为：1）通过体外匀浆结合测定法综合和评估对映体UCB-J类似物； 2） 在非人类素数中评估[18F] UCB-J的体内药代动力学和代谢概况 AIM 1的类似物； 3）使用SV2A PET成像来监测A 通过纵向多跟踪宠物成像和体内自显影术的AD转基因啮齿动物模型。 该项目的成功完成将产生一名宠物示踪剂，准备转换为诊所进行测试作为一个 生物标志物用于AD的早期检测。