MUSCARINIC RECEPTOR AGONISTS FOR STUDYING CNS DISORDERS

用于研究中枢神经系统疾病的毒蕈碱受体激动剂

基本信息

批准号：
2264426
负责人：
BARRY R ZEEBERG
金额：
$ 45.61万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-01-01 至 1995-02-28
项目状态：
已结题

项目摘要

This is a revised application to continue and extend our long-term objective to develop receptor-binding radiotracers for SPECT imaging of human brain. We propose a major new research direction by developing m2 subtype-selective receptor binding radioligands which can be applied to the in vivo study of regional concentrations of the m2 muscarinic receptor (mAChR) subtype in normal controls and in patients with CNS diseases. It is now apparent that quantitative detection of changes of cerebral concentrations of mAChR in Alzheimer's disease (AD) will require selectively imaging the m2 mAChR subtype, currently not possible with available radioligands. Therefore, we propose developing m2-selective radioligands based on the structure of AQ-RA 741, a potent m2-selective antagonist. Several alternative synthetic schemes are proposed to yield smaller and more lipophilic analogues of the parent compound that will be better able to cross the BBB. Each novel compound will be evaluated by apparent binding affinity and subtype-selectivity using a series of cell lines and tissues that each express a single mAChR subtype. Potent and subtype-selective compounds will be further evaluated for their ability to cross the BBB of mice using ex vivo binding studies, and if successful, will be radioiodinated and used further for biodistribution and pharmacokinetic studies in rats. We will perform pharmacokinetic modeling studies to determine whether the regional brain localization of the novel m2-selective radioligands will accurately reflect the regional brain m2 receptor concentration. This determination is required in order to validate that the regional m2 deficits expected in AD can be detectable in terms of a reduced regional radioligand localization. We will apply computer simulation studies of the SPECT, imaging process to a realistic model of the distribution of radioligand bound to m2 receptors in the brain. We will develop -an algorithm which can compensate for the distortions which we demonstrate in the SPECT imaging process, so that we will have the capability of performing quantitatively accurate SPECT neuroreceptor imaging. The proposed studies are designed to validate the quantitative potential of SPECT in studying CNS disorders, and to yield new information about disease states in living humans.

这是一个修订的应用程序，可继续并扩展我们的长期为了开发受体结合放射性示例的目的，以进行SPECT成像人脑。我们通过开发M2提出了一个主要的新研究方向亚型选择性受体结合可以应用于体内研究M2毒蕈碱受体的区域浓度（MACHR）正常对照和中枢神经系统疾病患者的亚型。它现在显然可以定量检测大脑变化阿尔茨海默氏病（AD）中MACHR的浓度将需要有选择地对M2 MACHR子类型进行成像，目前无法使用可用的放射线。因此，我们建议开发M2选择性基于AQ-RA 741的结构，有效的M2选择性对手。提出了几种替代合成方案来产生母体化合物的较小和更多的亲脂类似物更好地越过BBB。每个新颖的化合物将通过使用一系列细胞的表观结合亲和力和亚型选择性每个表达单一MACHR亚型的线条和组织。有效和亚型选择化合物的能力将进一步评估使用离体结合研究越过小鼠的BBB，如果成功，将被放射置并进一步用于生物分布和大鼠的药代动力学研究。我们将进行药代动力学建模研究，以确定是否新型M2选择性放射线的区域大脑定位将准确反映区域脑M2受体浓度。这为了验证区域M2是否需要确定可以根据减少的区域可检测到AD中预期的缺陷放射性物质定位。我们将对SPECT，成像过程的计算机模拟研究与M2受体结合的放射性物的分布的现实模型在大脑中。我们将开发一种可以补偿的算法我们在SPECT成像过程中证明的扭曲，以便我们将具有定量准确的SPECT的能力神经受体成像。拟议的研究旨在验证定量潜力研究中枢神经系统疾病的SPECT，并产生有关疾病状态在人类中。

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The distribution of cerebral muscarinic acetylcholine receptors in vivo in patients with dementia. A controlled study with 123IQNB and single photon emission computed tomography.

痴呆患者体内脑毒蕈碱乙酰胆碱受体的分布。

DOI：
10.1001/archneur.1991.00530140061018
发表时间：
1991
期刊：
Archives of neurology
影响因子：
0
作者：
Weinberger,DR;Gibson,R;Coppola,R;Jones,DW;Molchan,S;Sunderland,T;Berman,KF;Reba,RC
通讯作者：
Reba,RC

In vivo dissociation kinetics of [3H]quinuclidinyl benzilate: relationship to muscarinic receptor concentration and in vitro kinetics.

[3H]苯苯甲酸奎宁环酯的体内解离动力学：与毒蕈碱受体浓度和体外动力学的关系。