PET ANALYSIS OF DI-DOPAMINE RECEPTORS IN SCHIZOPHRENIA

精神分裂症二多巴胺受体的 PET 分析

• 批准号: 3486940
• 负责人: GORAN G SEDVALL
• 金额: $ 11.52万
• 依托单位: KAROLINSKA INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-02-01 至 1993-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3486940
• 关键词: antipsychotic agents; autoradiography; brain mapping; carbon; cerebral cortex; dopamine receptor; inhibitor /antagonist; limbic system; mental disorder chemotherapy; neuropharmacology; positron emission tomography; putamen; radionuclides; receptor binding; schizophrenia; substantia nigra

The broad long-term objectives of the application is to increase knowledge concerning pathophysiological mechanisms in the schizophrenias. The specific aim is to develop a PET-scan procedure for quantitative studies on the distribution, density and affinity characteristics of Dl- dopamine receptors in the major basal ganglia and other regions in the living human brain. The methodology will be applied to a comparison between Dl receptor characteristics in drug naive schizophrenic patients and healthy volunteers. Schizophrenic patients treated with chemically different types of antipsychotic drugs will also be examined with regard to Dl-dopamine receptor characteristics. Changes in Dl-dopamine receptor characteristics during long-term neuroleptic treatment and after the determination of such treatment will also be examined. For the PET- scanning procedure the highly potent and selective Dl-dopamine receptor antagonist SCH 23390 will be used. Our preliminary results indicate that this ligand, (1) has a high selectivity for Dl receptors, (2) has a high ratio of specific to non specific binding in vivo and (3) exhibits stereospecificity with regard to binding. This ligand has been shown to have excellent kinetic properties after intravenous administration to man for quantitative PET-scan analysis or Dl receptor characteristics as Bmax and Kd. Our preliminary results indicate saturability of 11-C-SCH 23390 binding to Dl receptors in the human putamen. Bmax-values in the order of 25 pmol/g tissue were obtained. These values are similar to those we obtained in preliminary experiments using the 3H-labelled ligand (eH-SCH 23390) in human putamen obtained postmortem. The project aims at comparing PET-scan results with regard to Dl-dopamine receptor characteristics with those obtained during in vitro conditions in schizophrenic patients and healthy volunteers. The project also aims at developing a quantitative autoradiographic technique based on the use of 11-C-labelled ligands. PET-scan experiments will be performed using our new high resolution PET camera system allowing the resolution of structures in the living human brain in the order of about 5 mm. This new camera system may allow quantitation of Dl-dopamine receptor characteristics also in several limbic and cortical cerebral areas as well as in large brain stem nuclei (substantia nigra) of living human subjects.

该申请的广泛长期目标是增加 关于精神分裂症病理生理机制的知识。 具体的目标是开发一种PET扫描程序， Dl-的分布、密度和亲和特性的研究 多巴胺受体的主要基底神经节和其他地区的 活的人脑 该方法将用于比较 未用药物的精神分裂症患者D1受体特征之间 健康的志愿者 精神分裂症患者用化学药物治疗 不同类型的抗精神病药物也将被检查， 多巴胺受体的特性。 DL-多巴胺受体的变化 长期精神抑制剂治疗期间和治疗后的特征 还将研究如何确定这种待遇。 对于PET- 扫描程序的高度有效和选择性的DL-多巴胺受体 将使用拮抗剂SCH 23390。 我们的初步结果表明， 该配体（1）对D1受体具有高选择性，（2）对D1受体具有高选择性， 体内特异性与非特异性结合的比率，和（3）表现出 关于结合的立体特异性。 该配体已被证明 人体静脉给药后具有优异的动力学特性 对于定量PET扫描分析或D1受体特征，如Bmax 的Kd。 我们的初步结果表明，饱和的11-C-SCH 23390 与人壳核中的D1受体结合。 Bmax值的顺序为 25 pmol/g组织。 这些价值观与我们 使用3 H-标记的配体（eH-SCH）在初步实验中获得 23390）在死后获得的人壳核中。 该项目旨在 比较PET扫描结果与DL-多巴胺受体 在体外条件下获得的特性， 精神分裂症患者和健康志愿者。 该项目还旨在 发展一种定量放射自显影技术， 11-C标记配体。 PET扫描实验将使用我们的 新的高分辨率PET相机系统， 在活的人脑中的结构在大约5毫米的顺序。这 新的照相机系统可以允许定量DL-多巴胺受体 特征也在几个边缘和皮质脑区， 以及在活体人类的大脑干核（黑质）中 科目