Preliminary imaging studies of the kappa opioid receptors in schizophrenia and their relationship to dopamine function

精神分裂症κ阿片受体及其与多巴胺功能关系的初步影像学研究

基本信息

批准号：
10304170
负责人：
Anissa Abi-Dargham
金额：
$ 19.94万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304170
关键词：
Agonist Alcohols Antipsychotic Agents Attention Biological Psychiatry Clinical Clinical Trials Corpus striatum structure Disease Disease remission Dopamine Dopamine D2 Receptor Dynorphins Female Functional disorder Heterogeneity Investigation Link MRI Scans Magnetic Resonance Imaging Marijuana Measures Mental disorders Methods Molecular Multimodal Imaging Naloxone Naltrexone Nicotine Noise Opioid Opioid Antagonist Pathway interactions Patient Selection Patients Pharmaceutical Preparations Pilot Projects Positron-Emission Tomography Proxy Psychoses Quality of life Recording of previous events Role Schizophrenia Severities Signal Transduction Smoking Substance Use Disorder Substantia nigra structure Symptoms System Testing Therapeutic Universities Up-Regulation Urine antagonist base biomarker-driven design healthy volunteer high reward high risk imaging study improved in vivo indexing kappa opioid receptors kappa receptors male neuroimaging neuromelanin neurotransmission novel novel therapeutics potential biomarker pre-clinical pre-clinical research racial and ethnic radiotracer salvinorin A therapeutic development therapeutic evaluation

项目摘要

Despite clinical and preclinical evidence suggesting a potential role for the kappa dynorphin system in schizophrenia, there are no rigorous in vivo investigations of this system in schizophrenia. We propose a multimodal imaging study to obtain information about the availability of kappa opioid receptors (KOR) in striatum in schizophrenia and explore its relationship to dopaminergic function measured in the same subjects, with a neuromelanin sensitive MRI (NM-MRI) scan. We recently validated NM-MRI as a measure of neuromelanin concentration and a marker of dopaminergic function, demonstrating a significant relationship between NM signal in the substantia nigra and Positron Emission Tomography measures of dopamine release capacity in the striatum. In this proposal 10 antipsychotic-drug naïve patients with schizophrenia and 10 demographically matched healthy controls will undergo a PET scan with [18F]LY2459989, a selective KOR antagonist radiotracer, and a NM-MRI scan to obtain in the same subjects a measure of KOR availability in the striatum and neuromelanin in the substantia nigra. We expect that groups will differ on both measures, and that upregulation of KOR will relate to higher neuromelanin in patients with SCZ. This pilot study will inform the design of a much larger study and provide POC for biomarker- driven investigations of KOR antagonists in schizophrenia by providing in vivo molecular measures and a link between KOR and dopamine dysfunction. This may ultimately provide support for advancing new therapeutic testing of specific KOR antagonists, informed by the use of potential biomarkers that we will probe here, the KOR and NM-MRI, to enhance the design and selection of patients with schizophrenia that could be targeted. New therapies are badly needed in this disease, particularly for patients in whom first-line D2-based treatments do not produce full remission of symptoms. Alternative or additional therapies to D2 drugs will improve the quality of life for patients suffering from this devastating disease.

尽管临床和临床前证据表明Kappa具有潜在的作用精神分裂症的dynorphin系统，对此没有严格的体内研究精神分裂症的系统。我们提出了一项多模式成像研究以获取信息关于精神分裂症的纹状体中的Kappa阿片受体（Kor）的可用性探索其与在同一受试者中测得的多巴胺能功能的关系， Neuromelanin敏感MRI（NM-MRI）扫描。我们最近将NM-MRI验证为神经丙氨酸浓度的度量和多巴胺能功能的标志物，证明了nigra的NM信号之间的显着关系，纹状体中多巴胺释放能力的正电子发射断层扫描量度。在该提议10抗精神分裂症患者和10例抗精神病药和10例人口统计匹配的健康对照将接受PET扫描 [18F] LY2459989，一种选择性的KOR拮抗剂radiotracer和NM-MRI扫描以获得在同一受试者中黑质尼格拉。我们预计团体在这两种措施上都会有所不同，并且 SCZ患者的KOR上调将与较高的神经苯胺有关。这个飞行员研究将为一项更大的研究的设计提供信息，并为生物标志物提供POC- 通过在体内提供对精神分裂症的KOR拮抗剂的驱动调查分子测量和多巴胺功能障碍之间的联系。这可能最终为推进特定kor的新治疗测试提供了支持通过使用潜在的生物标志物，我们将在这里探测的对抗者， KOR和NM-MRI，以增强精神分裂症患者的设计和选择那可能是针对的。在这种疾病中需要新的疗法，特别是一线基于D2治疗的患者无法完全缓解症状。 D2药物的替代或其他疗法将改善生活质量对于患有这种毁灭性疾病的患者。