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 该奖项的目标是促进申请人向该领域的独立研究者过​​渡 PET 神经影像专注于新型 PET 神经影像探针的开发和转化，用于早期诊断 申请人正在将他的研究重点从阿尔茨海默病（AD）的检测转向临床。 肿瘤学PET成像与神经影像PET显着不同。 申请人以前的培训，不仅在病理生理学方面，而且在图像采集方法方面，以及 特别是数据分析（图像处理、动力学建模）、示踪剂的特征（血脑屏障穿透、 培训计划包括重点关注的领域：药代动力学、代谢）和转化研究的动物模型。 课程作业、研讨会和会议，与 PET 神经影像探针领域的导师互动 开发、示踪动力学模型、抗 AD 药物开发和临床 AD 研究。 拟议的研究中，申请人将获得新技术，即离体放射自显影、图像处理、 申请人还将获得新技能，例如准备 IND 申请。 将显像剂转化为临床所必需的 拟议研究活动的目标是 开发用于 AD 早期检测的 18F 标记 PET 成像探针。 使用[11C]UCB-J获得的试点数据，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 为了克服 [11C]UCB-J 的局限性， 提议开发 18F 标记类似物用于临床转化 该提议的具体目标。 是： 1) 通过体外匀浆结合测定合成和评估对映体纯 UCB-J 类似物； 评估 [18F]UCB-J 在非人类灵长类动物中的体内药代动力学和代谢特征 目标 1 的类似物；3) 使用 SV2A PET 成像监测痴呆前 AD 进展情况 通过纵向多示踪剂 PET 成像和离体放射自显影技术建立 AD 转基因啮齿动物模型。 该项目的成功完成将产生 PET 示踪剂，可作为 早期检测 AD 的生物标志物。