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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 具有潜在作用精神分裂症中的强啡肽系统，目前还没有对此进行严格的体内研究精神分裂症的系统。我们提出多模态成像研究来获取信息关于精神分裂症患者纹状体中 kappa 阿片受体 (KOR) 的可用性以及探索其与在同一受试者中测量的多巴胺能功能的关系，神经黑色素敏感 MRI (NM-MRI) 扫描。我们最近验证了 NM-MRI 作为神经黑色素浓度的测量和多巴胺能功能的标记，证明黑质中的 NM 信号与正电子发射断层扫描测量纹状体中多巴胺的释放能力。在该提案针对 10 名未接受过抗精神病药物治疗的精神分裂症患者和 10 名人口统计匹配的健康对照将接受 PET 扫描 [18F]LY2459989，一种选择性 KOR 拮抗剂放射性示踪剂，通过 NM-MRI 扫描获得在同一受试者中，测量纹状体和神经黑色素中 KOR 的可用性黑质。我们预计不同群体在这两项措施上都会存在分歧，并且 KOR 的上调与 SCZ 患者神经黑色素的升高有关。这位飞行员研究将为更大规模的研究设计提供信息，并为生物标志物提供 POC 通过在体内提供 KOR 拮抗剂在精神分裂症中的驱动研究分子测量以及 KOR 和多巴胺功能障碍之间的联系。这可能最终为推进特定 KOR 的新治疗测试提供支持拮抗剂，通过使用我们将在这里探讨的潜在生物标志物来告知， KOR 和 NM-MRI，加强精神分裂症患者的设计和选择可以作为目标。这种疾病迫切需要新的疗法，特别是对于一线 D2 治疗未能使病情完全缓解的患者症状。 D2 药物的替代或附加疗法将改善生活质量对于患有这种毁灭性疾病的患者。