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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有潜在的作用