MUSCARINIC RECEPTOR AGENTS FOR STUDYING CNS DISORDERS

用于研究中枢神经系统疾病的毒蕈碱受体剂

• 批准号: 3404366
• 负责人: RICHARD C. REBA
• 金额: $ 64.05万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 1990-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3404366
• 关键词: Alzheimer's disease; acetylcholine; affinity chromatography; brain imaging /visualization /scanning; central nervous system disorders; chemical synthesis; cholinergic agents; drug metabolism; human subject; image processing; multiinfarct dementia; quinuclidines; radiopharmacology; single photon emission computed tomography; stereoisomer

The long term objective of this project is to develop single-photon emitting receptor binding radiotracers and implement methods for quantitating SPECT images of receptors in the brains of patients suffering from a variety of disorders which have been shown to affect receptor systems in the CNS. We are currently investigating the muscarinic acetylcholine receptor (m-AChR) with respect to changes in Alzheimer's disease and related disorders. Although this is a new proposal, we have imaged m-AChR in man using (R,R) (123I) 3-quinuclidinyl 4-iodobenzilate (41QNB), a high affinity m-AChR antagonist which we developed for myocardial imaging. But it is better suited for use in the CNS because there is a need for diagnostic tools which which provide information on receptor concentrations in brain. The objectives of this current proposal are to prepare in large quantities the precursor for synthesis of (R,R) and (R,S) (123I) 41QNB for use in clinical and biochemical studies. The (R,S) diastereomer provides different kinetic properties from those of the (R,R) diastereomer which may be more beneficial for the clinical studies. The clinical studies are suggested for a five year period; the patient populations to be examined are those with Alzheimer's disease, multi infarct dementia and Parkinson's disease. Normal subjects, age and sex matched, will be recruited from the families of patients when possible. The biochemical studies are designed to demonstrate that receptor concentration changes can be measured by the in vivo distribution of 41QNB. Changes are effected by a variety of lesioning techniques and the demonstration mapping by autoradiography. We will also establish the metabolic fate of (125I) 41QNB and the effect of decay on the compound and its receptor. In addition, we will provide the synthetic route for the synthesis of (11C) 3-quinuclidinyl atrolactate, a positron emitting radiotracer with many of the same properties as 41QNB. We will compare and contrast the images obtained using the two different radionuclides and technologies for their detection. The long term results of our pursuit of these goals will be an agent or agents which will be used for determining the change of receptor concentration of receptors in the CNS related to disease.

该项目的长期目标是开发单光子 发射受体结合放射性示例和实施方法 定量患者大脑中受体的SPECT图像 来自已证明会影响受体的多种疾病 中枢神经系统中的系统。 我们目前正在调查毒蕈碱 乙酰胆碱受体（M-ACHR）关于阿尔茨海默氏症的变化 疾病和相关疾病。 尽管这是一个新建议，但我们有 使用（r，r）（123i）3-核苷酸4-碘苯甲酸盐成像M-ACHR （41QNB），一种高亲和力M-ACHR拮抗剂，我们为 心肌成像。 但它更适合在中枢神经系统中使用 需要诊断工具，该工具提供有关 大脑中的受体浓度。 当前建议的目标 大量准备（R，R）和 （R，S）（123i）41QNB用于临床和生化研究。 （r，s） 非对映异构体提供与（R，R）的动力学特性不同的动力学特性 非对映异构体可能对临床研究更有益。 这 提出了五年的临床研究；病人 要检查的人群是患有阿尔茨海默氏病的人 梗死痴呆症和帕金森氏病。 正常受试者，年龄和性别 匹配，将在可能的情况下从患者家族中招募。 生化研究旨在证明受体 浓度变化可以通过体内分布来衡量 41QNB。 变化受各种病变技术的影响，并且 自显影映射的演示映射。 我们还将建立 （125i）41QNB的代谢命运以及衰减对化合物的影响 它的受体。 此外，我们将提供合成（11C）的合成途径 3-核苷酸阳性酸酯，一种正电子放射性示例，许多 与41QNB相同的属性。 我们将比较和对比图像 使用两种不同的放射性核素和技术获得 检测。 我们追求这些目标的长期结果将是代理商或 将用于确定受体变化的代理 中枢神经系统中与疾病有关的受体浓度。