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

尽管临床和临床前证据表明kappa蛋白在 强啡肽系统在精神分裂症中的作用，目前还没有严格的体内研究 精神分裂症的系统。我们提出了一个多模态成像研究，以获得信息 关于精神分裂症患者纹状体中κ阿片受体（KOR）的可用性， 探索其与多巴胺能功能的关系，在同一受试者中测量， 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志物， 证明了黑质中的NM信号与 正电子发射断层扫描测量纹状体多巴胺释放能力。在 该建议10名未经抗精神病药物治疗的精神分裂症患者和10名 人口统计学匹配的健康对照将接受PET扫描， [18F] LY 2459989，一种选择性KOR拮抗剂放射性示踪剂，和NM-MRI扫描，以获得 在相同的受试者中，测量纹状体中的KOR可用性和 黑质我们预计这两个群体在这两个方面都会有所不同， KOR的上调与SCZ患者中较高的神经黑色素有关。这一试点 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- 在精神分裂症中的KOR拮抗剂的驱动研究， 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，通过使用潜在的生物标志物，我们将在这里探测， KOR和NM-MRI，以加强精神分裂症患者的设计和选择 有可能成为目标这种疾病急需新的治疗方法，特别是对于 基于D2的一线治疗未产生完全缓解的患者 症状D2药物的替代或额外治疗将改善生活质量 为患有这种毁灭性疾病的患者提供帮助。

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.