Detection of Amyloid Plaques

描述(申请人提供)：这项研究项目的目标是确定配体的结构和放射性标记，这些配体将通过正电子(PET)或单光子(SPECT)发射断层扫描的外部成像，对活体大脑中的淀粉样蛋白位置进行定量测量。一种与淀粉样蛋白特异结合的放射性示踪剂将在阿尔茨海默病和相关老年病的诊断、监测、治疗和研究中发挥巨大的作用。基于经典构效关系方法的初步体外结合结果，我们发现某些苯并恶唑类化合物与淀粉样蛋白的亲和力在纳摩尔范围内。在这一应用中，我们建议检验以下假设：1)具有适当官能化芳香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；以及2)用PET或SPECT放射性核素标记将提供一种能够在体内成像淀粉样蛋白的分子探针。具体地说，本项目提出了以下具体目标：1.测量一组已合成的苯并噻唑类化合物与淀粉样蛋白的结合，以扩大这类化合物的构效关系。9个候选者将通过体外匀浆置换结合到放射性标记的淀粉样蛋白配体上进行测试。目的#2.合成已定义的卤代杂环类似物文库并筛选与淀粉样蛋白结合。工作假设是，成功的结构将包括连接到芳香族杂环5/6环系(B/C)上的芳环(A)上的供电子基的元素。11个候选者将被合成并通过体外匀浆置换结合到放射性标记的淀粉样蛋白配体上进行测试。目的#3.用放射性I-123或F-18标记最佳候选者，并测定它们在非人类灵长类动物体内的摄取特性。结合亲和力大于10 nM的候选者将被放射性标记，其亲油性将被测量为辛醇缓冲分配系数(LogD)。对数D小于3.5的化合物将通过SPECT或PET在非人类灵长类动物中进行动态区域脑成像研究。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，由淀粉样β蛋白(A？)多肽组成的丰富的老年斑和由高度磷酸化的tau蛋白细丝形成的神经原纤维缠结。因此，一种与A蛋白特异结合的放射性示踪剂将提供这一过程的活体测量，并将在精神疾病的研究、诊断和治疗中得到应用。在这一应用中，我们建议开发一种选择性化合物来定量人类的这些斑块。

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.