PET ANALYSIS OF D1 DOPAMINE RECEPTORS IN SCHIZOPHRENIA

描述（改编自申请人的摘要）： 该项目的目的是阐明D1样多巴胺受体在 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扫描程序进行定量放射性配体研究， D1类多巴胺受体存在于人类大脑的所有区域。 这 将采用方法复制和进一步发展 研究者初步发现D1多巴胺受体结合减少 在未用药的精神分裂症患者的大脑区域。 对于PET扫描 新的高亲和力和相对选择性的D1多巴胺 受体拮抗剂（11 C）NNC 112将被使用。 调查人员 初步结果表明，该配体具有较高的 特异性结合至非特异性结合和其它优点， 研究者先前开发的放射性配体（11 C）SCH 23390。 这允许 在一些边缘系统和新皮层中D1密度的定量 健康人和精神分裂症患者基底节区以外的脑区 科目 第二个具体目标是系统地将PET方法联合收割机与 人类死后大脑研究 控制组的整个大脑半球， 精神分裂症受试者将被冷冻切片，以提供多达1 每个大脑的500个半球切片 这些连续的部分将 允许开发D1的全面详细的定量地图 使用（3 H）NNC在人脑所有区域中的多巴胺受体结合 112. 这些尸检材料也将被并行处理， D1和D5多巴胺基因信息的定量分布 受体和相关蛋白在整个人脑中通过原位 杂交组织化学 PET扫描实验将使用研究者的新3D 西门子ECAT HR 47 PET摄像系统， 在活的人脑中的结构下降到约3-4 mm的数量级。 将检索尸检研究放射自显影图像信息 通过高分辨率视频摄像机系统允许量化， 在大脑所有区域中的D1多巴胺受体特征的可视化 人类实验对象的分辨率降低到50微米。 PET和尸检分析的完整图像数据集将 通过快速高容量计算机介质（硅）存储和处理 图形），用于构建第一个快速访问的定量 关于D1样多巴胺受体特征的3D信息库 在健康人和精神分裂症患者的大脑中。

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.