PET ANALYSIS OF D1 DOPAMINE RECEPTORS IN SCHIZOPHRENIA

描述(改编自申请人的摘要)： 该项目旨在阐明D1样多巴胺受体在脑出血中的作用。 精神分裂症的病理生理学。具体目标是进一步发展 并应用PET扫描程序对放射性配基进行定量研究 在人类活体大脑的所有区域都有类似于D1型的多巴胺受体。这 将采用方法论来复制和进一步发展 研究人员初步发现D1多巴胺受体结合减少 在未服药的精神分裂症患者的大脑区域。用于正电子发射计算机断层扫描 新的高亲和力和相对选择性的D1多巴胺 将使用受体拮抗剂(11C)NNC 112。调查人员的 初步结果表明，该配体具有较高的比例。 特定于非特定绑定以及与 研究人员先前开发的放射性配体(11C)SCH 23390。这使得 几种边缘皮质和新皮质中D1密度的定量 正常人和精神分裂症患者基底节以外的脑区 研究对象。 第二个具体目标是系统地将PET方法与 人类尸检脑部研究。从控制和控制的整个半球 精神分裂症患者将被广泛冷冻，以提供最多1 取自每个大脑的500个半球切片。这些连续的部分将 允许开发全面的详细量化地图的第1位 用(~3H)NNC法研究人脑各区域的多巴胺受体结合 112.这些尸检材料也将被并行处理以探索 多巴胺D_1和D_5基因信息的定量分布 原位观察人脑组织中的受体和相关蛋白 杂交组织化学。 PET扫描实验将使用研究人员的新3D 收购西门子ECAT HR 47 PET摄像系统，允许分辨率 活着的人脑中的结构大约为3-4毫米。为 将检索尸检放射自显影图像信息 通过高分辨率摄像机系统允许量化和 脑部各区域D1多巴胺受体特征的可视化研究 人类受试者的分辨率降到了大约50微米。 来自PET和尸检分析的完整图像数据集将是 通过快速大容量计算机介质(硅)进行存储和处理 图形)用于构建第一个可快速访问的量化 关于D1样多巴胺受体特性的3D信息库 在健康和精神分裂症的个体受试者的大脑中。

DESCRIPTION (Adapted from applicant's abstract): The broad objective of the project is to clarify the role of D1-like dopamine receptors in the pathophysiology of schizophrenia. The specific aim is to further develop and apply PET scan procedures for quantitative radioligand studies on D1-like dopamine receptors in all areas of the human living brain. This methodology will be applied to replicate and further develop the investigator's preliminary finding of reduced D1 dopamine receptor binding in brain regions of drug-naive schizophrenic patients. For the PET scanning procedure the new high affinity and relatively selective D1 dopamine receptor antagonist (11C)NNC 112 will be used. The investigators's preliminary results have demonstrated that this ligand has a higher ratio of specific to nonspecific binding and other advantages as compared to the investigator's previously developed radioligand (11C)SCH 23390. This allows the quantification of D1-densities in a number of limbic and neocortical regions besides the basal ganglia in living healthy and schizophrenic subjects. The second specific aim is to systematically combine the PET approach with human postmortem brain studies. Whole hemispheres from control and schizophrenic subjects will be cryosectioned in extenso to provide up to 1 500 hemisphere sections from each brain. These consecutive sections will allow the development of comprehensive detailed quantitative maps of D1 dopamine receptor binding in all regions of the human brain using (3H) NNC 112. This postmortem material will also be processed in parallel to explore the quantitative distribution of the gene messages for D1 and D5 dopamine receptors and related proteins throughout the human brain by in situ hybridization histochemistry. The PET scan experiments will be performed using the investigator's new 3D acquisition Siemens ECAT HR 47 PET camera system allowing the resolution of structures in the living human brain down to the order of about 3-4 mm. For the postmortem studies autoradiographic image information will be retrieved by a high resolution video camera system allowing the quantification and visualization of D1 dopamine receptor characteristics in all areas of brain of human subjects down to a resolution of about 50 microns. The complete sets of image data from PET and postmortem analyses will be stored and processed by means of fast high capacity computer media (Silicon Graphics) for the construction of the first rapidly accessible quantitative 3D information banks concerning D1-like dopamine receptor characteristics throughout the brain of individual healthy and schizophrenic human subjects.