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，这些配体将通过正电子（PET）或单光子（SPECT）发射断层扫描进行活体脑中淀粉样蛋白位点的定量测量。与淀粉样蛋白特异性结合的放射性示踪剂在阿尔茨海默病及相关老年疾病的诊断、监测、治疗和研究中具有重要的应用价值。基于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衍生物与淀粉样蛋白在纳摩尔范围内具有亲和力。在这个应用中，我们建议测试以下假设：1)具有适当功能化芳香取代基的新型吲哚和苯并咪唑衍生物有利于与淀粉样蛋白Ab（1-40）结合；2)用PET或SPECT放射性核素进行放射性标记将提供一种分子探针，可以在体内对淀粉样蛋白进行成像。具体来说，这个项目提出了以下具体目标AIM #1。测量已合成的一组苯并噻唑衍生物与淀粉样蛋白的结合，以扩大这类化合物的构效关系。9个候选药物将通过体外均质置换结合与放射性标记的淀粉样蛋白配体进行测试。目标# 2。合成一个确定的卤化杂环类似物库，并筛选与淀粉样蛋白的结合。工作假设是，成功的结构将在芳香环(A)上结合给电子基的元素，并连接到芳香杂环（B/C）上。十一种候选蛋白将通过体外均质置换结合与放射性标记的淀粉样蛋白配体进行合成和测试。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，并测定其在非人灵长类动物体内的吸收特性。结合亲和度大于10 nM的候选物质将被放射性标记，其亲脂性将被测量为辛醇缓冲分配系数（log D）。logd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区域脑成像来研究。我们估计每年将对四种化合物进行成像。阿尔茨海默病（AD）的病因尚不清楚，但对患者大脑的尸检检查显示，由淀粉样蛋白- β （A¿）肽和由高度磷酸化的tau蛋白细丝形成的神经原纤维缠结组成的大量老年斑。因此，与a¿蛋白特异性结合的放射性示踪剂将提供这一过程的体内测量，并将在精神疾病的研究、诊断和治疗中得到应用。在这个应用中，我们建议开发一种选择性化合物来量化人类中的这些斑块。

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.