DEVELOPMENT OF A PET RADIOTRACER FOR SIGMA-1 RECEPTOR

开发 Sigma-1 受体 PET 放射示踪剂

• 批准号: 6189975
• 负责人: RIKKI Noel WATERHOUSE
• 金额: $ 25.71万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6189975
• 关键词: baboons; bioimaging /biomedical imaging; brain imaging /visualization /scanning; clinical research; drug receptors; human subject; opioid receptor; positron emission tomography; radiotracer; schizophrenia; technology /technique development

Sigma-1 receptors are found throughout the central nervous system. Recent studies provide evidence for a role of sigma-1 receptors in schizophrenia. First, postmortem studies using the most selective radioligands have consistently revealed a decrease in sigma receptor density in the frontal cortex of schizophrenics compared to controls. Second, agonist binding at sigma-1 receptors facilitates N-methyl-D-aspartate (NMDA) stimulated dopamine release. In vivo, the release of dopamine evoked by sigma agonists occurs in the prefrontal cortex, a region where dopamine is intimately involved in the pathophysiology of negative and cognitive symptoms of the illness. Third, phase I clinical trials have indicated that atypical sigma-1 binding neuroleptics are effective in alleviating negative symptoms in some schizophrenics. Together, these data suggest that, in schizophrenia, alterations in sigma-1 receptor function might be associated with a deficit in glutamatergic and dopamine function in the prefrontal cortex. Yet, interpretation of postmortem changes in sigma-1 receptors has proven difficult, since most schizophrenics are on treatment prior to death. Therefore, Positron Emission Tomography (PET) measurement of sigma-1 receptors in drug-naive patients is critically needed to verify the decrease in sigma-1 receptor density in schizophrenia. PET methods are also essential to correlate sigma-1 receptor occupancy with the therapeutic or side effects of sigma-1 binding neuroleptics. The PI has designed a novel sigma-1 PET ligand, [18F]FPS, which has appropriate lipophilicity, stability, receptor affinity and selectivity to allow the accurate characterization sigma-1 receptors in vivo. Preliminary PET imaging experiments in non-human primates has confirmed the potential of this tracer to quantify sigma-1 receptors in the brain. An excellent correlation (R2=0.985) was observed between regional binding potential and reported sigma receptor densities in seven brain regions. The aim of this proposal is to fully develop [18F]FPS, including imaging and blocking experiments in baboons, toxicity studies and dosimetry estimates. In addition, the characterization of [18F]FPS binding in humans will be carried out. Upon successful completion of this work, clinical studies using this radiotracer will be proposed. The ability to measure sigma-1 receptors with PET is important, not only for schizophrenia, but also for other clinical indications, in which sigma receptor function is highly implicated, including disturbances in cognitive function and memory, and tumor imaging.

Sigma-1 受体遍布中枢神经系统。 最近的研究提供了 sigma-1 受体在 精神分裂症。首先，使用最具选择性的放射性配体进行尸检研究 一致揭示额叶西格玛受体密度下降 精神分裂症患者的皮质与对照组相比。第二，激动剂结合 sigma-1 受体促进 N-甲基-D-天冬氨酸 (NMDA) 刺激的多巴胺 发布。在体内，西格玛激动剂引起的多巴胺释放发生在 前额叶皮层，多巴胺密切参与的区域 该疾病的阴性症状和认知症状的病理生理学。三、阶段 I 临床试验表明非典型 sigma-1 结合精神安定药 可有效缓解某些精神分裂症患者的阴性症状。一起， 这些数据表明，在精神分裂症中，sigma-1 受体的改变 功能可能与谷氨酸和多巴胺缺乏有关 功能在前额皮质。然而，对尸检变化的解释 sigma-1 受体已被证明是困难的，因为大多数精神分裂症患者都处于 死亡前的治疗。因此，正电子发射断层扫描（PET） 迫切需要测量未接受过药物治疗的患者的 sigma-1 受体 验证精神分裂症中 sigma-1 受体密度的降低。正电子发射断层扫描法 对于将 sigma-1 受体占用率与治疗相关联也至关重要 或 sigma-1 结合精神安定药的副作用。 PI设计了一部小说 sigma-1 PET配体，[18F]FPS，具有适当的亲脂性、稳定性、 受体亲和力和选择性，以实现准确的表征 体内的 sigma-1 受体。非人类的初步 PET 成像实验 灵长类动物已证实该示踪剂量化 sigma-1 的潜力 大脑中的受体。观察到良好的相关性 (R2=0.985) 区域结合潜力和报告的 sigma 受体密度之间 七个大脑区域。该提案的目的是充分开发[18F]FPS， 包括狒狒成像和阻断实验、毒性研究和 剂量测定估计。此外，[18F]FPS 结合的表征 人类将被执行。成功完成这项工作后，临床 将提出使用这种放射性示踪剂的研究。测量 sigma-1 的能力 PET 受体不仅对于精神分裂症很重要，对于其他疾病也很重要。 西格玛受体功能高度相关的临床适应症， 包括认知功能和记忆障碍以及肿瘤成像。