Detection of Amyloid Plaques

描述（由申请人提供）：本研究项目的目标是定义配体的结构和放射性标记，这些配体将允许通过正电子（PET）或单光子（SPECT）发射断层扫描的外部成像定量测量活脑中的淀粉样蛋白位点。特异性结合淀粉样蛋白的放射性示踪剂将在阿尔茨海默病和相关老年疾病的诊断、监测治疗和研究中具有很大的实用性。基于使用经典的结构-活性关系方法的初步体外结合结果，我们发现某些苯并恶唑衍生物在纳摩尔范围内对淀粉样蛋白表现出亲和力。在本申请中，我们提出测试以下假设：1）具有适当官能化的芳族取代基的新型吲哚和苯并咪唑衍生物将有利于与淀粉样蛋白Ab（1-40）蛋白结合;和2）用PET或SPECT放射性核素进行放射性标记将提供可以在体内使淀粉样蛋白成像的分子探针。具体而言，该项目提出了以下具体目标AIM #1。测量已经合成的一组苯并噻唑衍生物与淀粉样蛋白的结合，以扩展这类化合物的结构-活性关系。将通过体外匀浆置换结合放射性标记的淀粉样蛋白配体检测9种候选物。目标#2。合成卤代杂环类似物的确定文库并筛选与淀粉样蛋白的结合。工作假设是，成功的结构将在连接到芳族杂环5/6环系统（B/C）的芳环（A）上引入给电子基团的元素。将合成11种候选物，并通过体外匀浆置换结合放射性标记的淀粉样蛋白配体进行检测。目标#3。用放射性I-123或F-18对最佳候选物进行放射性标记，并确定其在非人灵长类动物体内的摄取特性。将对结合亲和力优于10 nM的候选物进行放射性标记，并将其亲脂性测量为辛醇缓冲液分配系数（log D）。log D小于3.5的化合物将通过SPECT或PET在非人灵长类动物中进行动态局部脑成像研究。我们估计每年将有四种化合物被成像。阿尔茨海默病（AD）的病因尚不清楚，但对患者大脑的尸检显示，患者大脑中存在大量由淀粉样β（A？）肽组成的老年斑和由高度磷酸化的tau蛋白细丝形成的神经元缠结。因此，特异性结合A蛋白的放射性示踪剂将提供该过程的体内测量，并将在精神疾病的研究、诊断和治疗中找到应用。在本申请中，我们提出开发一种选择性化合物来定量人体中的这些斑块。

DESCRIPTION (provided by applicant): The goal of this research project is to define the structure and radioactive label for ligands that will per-mit quantitative measurement of amyloid sites in living brain by external imaging with positron (PET) or single photon (SPECT) emission tomography. A radiotracer that bound specifically to amyloid would be of great utility in diagnosis, monitoring treatment, and research of such Alzheimer's disease and related gerontological disorders. Based on preliminary in vitro binding results using a classical structure-activity relationship approach, we found that certain benzoxazole derivatives showed affinity to amyloid protein in the nanomolar range. In this application we propose to test the following hypotheses: 1) Novel Indole and benzimidazole derivatives with appropriately functionalized aromatic substituents will favor binding to amyloid Ab(1-40) protein; and 2) radio-labeling with PET or SPECT radionuclides will provide a molecular probe that can image amyloid protein in vivo. Specifically, this project poses the following specific aims AIM #1. Measure binding to amyloid protein of a group of benzothiazole derivatives already synthesized to expand the structure-activity relationship in this class of compounds. Nine candidates will be tested by in vitro homogenate displacement binding against radiolabeled ligand for amyloid protein. AIM #2. Synthesize a defined library of halogenated heterocyclic analogs and screen for binding to amyloid protein. The working hypothesis is that the successful structure will incorporate the elements of an electron-donating group on an aromatic ring (A) attached to an aromatic heterocyclic 5/6 ring system (B/C). Eleven candidates will be synthesized and tested by in vitro homogenate displacement binding against radiolabeled ligand for amyloid protein. AIM #3. Radiolabel the best candidates with radioactive I-123 or F-18 and determine their in vivo uptake properties in nonhuman primates. The candidates with binding affinities better than 10 nM will be radiolabeled and their lipophilicity will be measured as the octanol-buffer partition coefficient (log D). Compounds with log D less than 3.5 will be studied by dynamic regional brain imaging in nonhuman primates by with SPECT or PET. We estimate that four compounds per year will be imaged. The causes of Alzheimer's disease (AD) are still unclear, but postmortem examination of patient's brains reveal abundant senile plaques composed of amyloid-beta (A¿) peptides and neurofibrillary tangles formed by filaments of highly phosphorylated tau protein. Thus, a radiotracer that bound specifically to A¿ protein would provide an in vivo measure of this process and would find application in the study, diagnosis, and treatment of psychiatric disorders. In this application we proposed to develop a selective compound to quantify these plaques in human.