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

摘要 这一奖项的目标是促进申请者向独立调查员的转变 早期PET神经影像--新型PET神经影像探针的开发与翻译 阿尔茨海默病(AD)的检测到临床。申请者正在将他的研究重点从 肿瘤正电子发射计算机断层成像到正电子发射计算机断层成像。而新的方向与 申请人以前的培训，不仅在病理生理学方面，而且在图像获取方法方面，以及 特别是数据分析(图像处理、动力学建模)、示踪剂特性(血脑屏障渗透率、 药代动力学、新陈代谢)和用于转译研究的动物模型。培训计划包括重点培训 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、示踪剂动力学建模、抗AD药物开发和临床AD研究。通过 在拟议的研究中，申请人将获得新的技术，即体外放射自显影，图像处理， 和动力学建模。申请者还将获得新的技能，如准备IND申请，这是 是将显像剂转化为临床所必需的。拟议研究活动的目标是 研制用于AD早期检测的18F-PET显像剂。建议的研究项目是基于 基于使用[11C]UCB-J获得的试点数据，这证明了 将SV2a作为临床前或先兆AD的生物标志物。为了克服[11C]UCB-J的限制， 建议开发18F标记类似物用于临床翻译。该提案的具体目的 目的：1)通过体外匀浆结合实验，合成和鉴定手性UCB-J类似物；2) 评价[18F]UCB-J在非人灵长类动物体内的药代动力学和代谢特征 类似物从目标1；3)使用SV2APET成像来监测痴呆前期AD的进展 通过纵向多示踪PET成像和体外放射自显影建立转基因AD动物模型。 该项目的成功完成将产生一种PET示踪剂，准备转化到临床进行测试 用于AD早期检测的生物标志物。

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.