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.

摘要 该奖项的目标是促进申请人在该领域的独立调查员的过渡 PET神经成像专注于开发和翻译新型PET神经成像探针，用于早期诊断 老年痴呆症（AD）的诊断申请人将研究重点从 肿瘤PET成像到PET神经成像。新的方向与 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），示踪剂的特性（BBB渗透， 药代动力学、代谢）和用于转化研究的动物模型。培训计划包括： 课程、研讨会和会议，与PET神经成像探头领域的导师互动 开发、示踪动力学建模、抗AD药物开发和临床AD研究。通过 申请人将获得新的技术，即，离体放射自显影，图像处理， 和动力学建模。申请人还将获得新的技能，如准备IND申请， 是将成像剂转移到临床所必需的。拟议研究活动的目标是 开发18F标记的PET成像探针用于早期检测AD。该研究项目基于 使用[11 C]UCB-J获得的初步数据，证明了 将SV 2A成像为临床前或前驱AD的生物标志物。为了克服[11 C]UCB-J的局限性， 18F标记的类似物被建议开发用于临床翻译。提案的具体目标 目的：1）通过体外匀浆结合试验合成和评价对映体纯的UCB-J类似物; 2） 在非人灵长类动物中评价[18 F] UCB-J的体内药代动力学和代谢特征 3）使用SV 2A PET成像监测老年痴呆症患者的痴呆前AD进展， 通过纵向多示踪剂PET成像和离体放射自显影，对AD的转基因啮齿动物模型进行了研究。 该项目的成功完成将产生一个PET示踪剂，准备翻译到诊所进行测试， 用于早期检测AD的生物标志物。