SPECT IMAGING OF 5HT1A RECEPTOR

5HT1A 受体的 SPECT 成像

• 批准号: 6591363
• 负责人: Bertha K Madras
• 金额: $ 11.11万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6591363
• 关键词: animal tissue; bioimaging /biomedical imaging; mental disorders; nervous system; pharmacology; proteins; radiology; spectrometry; technology /technique

Brain serotonin receptors are implicated in psychiatric disorders, particularly depression, anxiety and substance abuse Of the 14 subtypes of serotonin receptors identified in brain, the 5HT-1A receptor is a direct target of the atypical anti-anxiety drug buspirone and an indirect target of antidepressant drugs To determine the feasibility of monitoring this receptor in living brain by SPECT imaging, we investigated rhenium analogues of WAY 100635 WAY 100635 is an aryl piperazine that previously has been identified as a PET ligand for brain 5HT1A serotonin receptors In an effort to optimize the affinity and brain uptake of these metal-chelated analogues, several compounds were synthesized with various linkers between the receptor binding moiety and two N2S2 chelate systems In vitro assays of the complexes were conducted in frontal cortex of brain using [3H]8-OH-DPAT a 5HT1A ligand and [3H]7-OH-DPAT to label the D3 dopamine receptor Several compounds displa yed nanomolar affinity for the 5HT1A receptor and one compound was potent at the D3 dopamine receptor Further research on brain uptake and biodistribution is planned in small mammalian species Our successful imaging of the brain dopamine transporter with technetium-labeled probes may extend to other proteins of therapeutic or diagnostic relevance Alan J Fischman, MD, Ph D Department of Nuclear Medicine, Radiology, Massachusetts General Hospital, Boston, MA To develop and evaluate novel PET and SPECT imaging agents as markers for dopamine neurons in Parkinson's disease and other brain disorders To conduct clinical trials with altropane To determine brain occupancy of candidate cocaine medications To determine the effects of chronic administration of candidate medications on brain dopamine systems To evaluate the brain occupancy pf a novel candidate antiparkinsonian drug To develop novel technetium agents Ali Bonab, Ph D , Massachusetts General Hospital Boston, MA Nat Alpert, Ph D , Massachusetts General Hospital Boston, MA To develop methods for quantifying the dopamine transporter using PET imaging of brain Anna-Liisa Brownell, Ph D , Department of Radiology ,Massachusetts General Hospital ,Boston, MA To conduct PET imaging studies with novel and other compounds, for probing the targets of cocaine Peter C Meltzer, Ph D , Organix, Inc Paul Blundell, Ph D To synthesize and evaluate novel tropanes as probes for monoamine transporters, as imaging agents and as therapeutics for cocaine medications and Parkinson's disease To develop novel technetium agents Aloke Dutta, Ph D , Organix, Inc To develop potent and selective GBR analogs for the dopamine transporter Alun G Jones, Ph D , Harvard Medical School Ashfaq Mahmood, Ph D , Harvard Medical School To develop technetium imaging agents for brain dopamine and serotonin systems Alan Davison, Ph D , Massachusetts Institute of Technology To develop technetium imaging agents for brain dopamine and serotonin systems Jack Bergman, Ph D , McLean Hospital, Belmont, MA To measure the effects of chronic cocaine on dopamine systems in brain Allyn C Howlett, Ph D St Louis University, St Louis MO To investigate cannabinoid/dopamine agonists interaction To assess therapeutic potential of cannabinoid antagonists Susan Amara, Mark Sonders, Vollum Institute, Portland OR To determine effects of novel drugs on currents in cells transfected with transporters Susan George, M D , University of Toronto Brian O'Dowd, Ph D ,University of Toronto To measure effects of non-amines on extracellular dopamine levels in vivo Beth Hoffman, Ph D NIH To develop point mutations on the dopamine transporter Philip Seeman, M D , Ph D To develop novel hypotheses on mechanism of action of anti-hyperactivity medications

大脑血清素受体与精神疾病有关， 尤其是抑郁、焦虑和药物滥用 在 14 人中 大脑中发现的血清素受体亚型 5HT-1A 受体是非典型抗焦虑药物的直接靶点 丁螺环酮和抗抑郁药物的间接靶点 确定 通过 SPECT 监测活体大脑中该受体的可行性 成像，我们研究了 WAY 100635 的铼类似物 WAY 100635 是 先前已被确定为 PET 配体的芳基哌嗪 对于大脑 5HT1A 血清素受体，努力优化 这些金属螯合类似物的亲和力和大脑吸收 合成了受体之间具有各种连接体的化合物 结合部分和两个 N2S2 螯合系统 的体外测定 复合物是在大脑额叶皮质中进行的 [3H]8-OH-DPAT 5HT1A 配体和 [3H]7-OH-DPAT 标记 D3 多巴胺受体 几种化合物对多巴胺受体表现出纳摩尔亲和力 5HT1A 受体和一种化合物对 D3 多巴胺有效 受体大脑摄取和生物分布的进一步研究是 计划在小型哺乳动物中进行 我们成功的大脑成像 带有锝标记探针的多巴胺转运蛋白可能延伸至 其他具有治疗或诊断相关性的蛋白质 Alan J Fischman， 马萨诸塞州放射科核医学系医学博士、博士 马萨诸塞州波士顿综合医院 开发和评估新型 PET 和 SPECT 成像剂作为帕金森病多巴胺神经元的标记物 疾病和其他脑部疾病进行临床试验 阿托烷 确定候选可卡因的大脑占用率 药物 确定长期服用药物的效果 大脑多巴胺系统的候选药物 评估大脑 占据一种新型候选抗帕金森病药物 开发新型药物 锝剂 Ali Bonab，博士，马萨诸塞州总医院 波士顿，马萨诸塞州 Nat Alpert 博士，马萨诸塞州总医院波士顿， MA 开发定量多巴胺转运蛋白的方法 大脑 PET 成像 Anna-Liisa Brownell 博士，系 放射科，马萨诸塞州总医院，波士顿，马萨诸塞州 进行 PET 新型化合物和其他化合物的成像研究，用于探测 可卡因的目标 Peter C Meltzer 博士，Organix, Inc Paul Blundell， 博士 合成和评估作为单胺探针的新型托烷类 转运蛋白，作为显像剂和可卡因治疗剂 药物和帕金森病 开发新型锝剂 Aloke Dutta 博士，Organix, Inc 开发有效且选择性的 GBR 多巴胺转运蛋白类似物 Alun G Jones，哈佛大学博士 医学院 Ashfaq Mahmood 博士，哈佛医学院 开发大脑多巴胺和血清素的锝显像剂 系统 Alan Davison，博士，麻省理工学院 开发大脑多巴胺和血清素的锝显像剂 Jack Bergman 博士，马萨诸塞州贝尔蒙特麦克莱恩医院系统 测量 长期吸食可卡因对大脑多巴胺系统的影响 Allyn C Howlett 博士 圣路易斯大学，密苏里州圣路易斯 调查 大麻素/多巴胺激动剂相互作用 评估治疗效果 大麻素拮抗剂的潜力 Susan Amara、Mark Sonders、Vollum 俄勒冈州波特兰研究所 确定新药对电流的影响 在用转运蛋白转染的细胞中 Susan George，医学博士，大学 多伦多大学 Brian O'Dowd 博士 测量 非胺类物质对体内细胞外多巴胺水平的影响 Beth 霍夫曼博士 NIH 开发多巴胺点突变 转运蛋白 Philip Seeman，医学博士、博士 提出关于 抗多动药物的作用机制