Development of PET Probes for Quantifying Metabotropic Glutamate-1 Receptors

用于定量代谢型 Glutamate-1 受体的 PET 探针的开发

基本信息

批准号：
8064421
负责人：
J. S. Dileep KUMAR
金额：
$ 23.79万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-19 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8064421
关键词：
Adult Affinity Animals Anxiety Autopsy Autoradiography Binding Binding Sites Biodistribution Biological Assay Biological Markers Biological Markers Biological Process Blood Blood - brain barrier anatomy Brain Brain region Cerebellum Cerebral cortex Cognition Disorders Commit Data Depressive disorder Detection Development Diagnosis Dissection Drug Delivery Systems Ensure Epilepsy Equilibrium Evaluation Functional disorder G-Protein-Coupled Receptors Glutamates High Pressure Liquid Chromatography Hippocampus (Brain)Human Image Image Analysis Imaging Techniques In Vitro Ischemia Kinetics Label Lead Learning Ligand Binding Ligands Measures Mediating Memory Mental Depression Mental disorders Metabolism Metabotropic Glutamate Receptors Methods Modeling Molecular Monitor Motor Multiple Sclerosis National Institute of Mental Health Neuraxis Neurons Neurotransmitters One-Step dentin bonding system Papio Permeability Pharmaceutical Preparations Pharmacology Phase Physiological Plasma Play Positron Positron-Emission Tomography Preclinical Drug Evaluation Preparation Product Labeling Psychotropic Drugs Radioactivity Radioisotopes Radiolabeled Rattus Receptor Activation Reproducibility Role Scanning Scheme Selection Criteria Site Slide Specificity Staging Study models Synapses Synaptic plasticity System Testing Thalamic structure Therapeutic Agents Therapeutic Effect Therapeutic Intervention Time TimeLine Tissues Tracer Validation Work analog base design drug development flexibility imaging probe improved in vivo interest lipophilicity man meetings metabotropic glutamate receptor type 1 nervous system disorder nonhuman primate novel novel therapeutics painful neuropathy postsynaptic preclinical study programs public health relevance radiochemical radioligand radiotracer receptor research and development research study response success therapeutic development tool uptake

项目摘要

DESCRIPTION (provided by applicant): Metabotropic glutamate 1 receptors (mGluR1) are G-protein coupled receptors and are expressed in many central nervous system regions, especially in cerebellum, cerebral cortex, hippocampus and thalamus. Several studies have shown that mGluR1 plays a crucial role in synaptic plasticity, learning and memory and motor coordination. Over activation of this receptor has been implicated in neurological and psychiatric disorders such as ischemia, epilepsy, anxiety, depressive disorders, multiple sclerosis and neuropathic pain. As a result mGluR1s have been the targets of intensive drug development research. A Positron Emission Tomography (PET) ligand would be a biological marker to detect alterations in mGluR1 in vivo and non-invasively. In view of this many groups have attempted to develop a specific PET tracer with limited success. Therefore, the objective of the proposed study is to develop a PET tracer to non-invasively monitor in vivo binding to the mGluR1 from rats to non-human primates. We propose three new mGluR1 antagonists 1, 2, and 3 (Figure 2) as candidates for PET tracer development based on their excellent affinity to mGluR1, adequate logP values that allow facile entry to brain, availability of suitable labeling sites and promising in vivo pharmacology data available. We accomplished the synthesis of [11C] 1 in good yield and specific activity. Our initial autoradiography studies in slide mounted sections of postmortem human brain resulted in specific binding of [11C] 1 to mGluR1 enriched brain regions (section 4). In this application, therefore, we propose to complete the characterization of [11C] 1 through rats and baboon studies such that the next phase of work would be related to use in man. [11C] 1 is a promising lead tracer and its analogues 2 and 3 are also selected as alternate compounds. Blocking studies with the known mGluR1 antagonist JNJ16259685 will be performed to obtain specific binding in rats and baboon. [11C] 2 and [11C] 3 will also be synthesized as alternative ligands and studied successively if [11C] 1 fails to meet the criteria of a specific PET tracer for mGluR1. The optimal PET tracer will be identified for modeling studies and to develop methods for the quantification of mGluR1 in man. The selection criteria of candidate PET tracers for testing, and the strategies proposed for the identification of the most successful tracer is given in sections 5. At the end of the proposed studies we anticipate to have a PET tracer as potential tool for in vivo human studies of mGluR1, and to obtain occupancy of drugs that have affinity to mGluR1. PUBLIC HEALTH RELEVANCE: Metabotropic glutamate 1 receptor (mGluR1s) are involved in the pathophysiology of epilepsy, ischemia, anxiety, depression and neuropathic pain and by using Positron Emission Tomography (PET) it is possible to measure changes in a receptor system in vivo non-invasively and quantitatively in molecular level. To date there is no successful PET tracer for the /in vivo/ quantification of mGluR1. Therefore, we are committed to develop a specific PET tracer for mGluR1 as a potential tool for human studies of psychiatric illnesses and for novel drug development

描述（由申请人提供）：代谢型谷氨酸1受体（MGLUR1）是G蛋白偶联受体，并且在许多中枢神经系统区域表达，尤其是在小脑，大脑皮层，海马和海马和丘脑中。几项研究表明，MGLUR1在突触可塑性，学习和记忆和运动配位中起着至关重要的作用。该受体的激活与神经系统和精神疾病有关，例如缺血，癫痫，焦虑，抑郁症，多发性硬化症和神经性疼痛。结果，MGLUR1是强化药物开发研究的目标。正电子发射断层扫描（PET）配体将是一种生物学标记物，可在体内和非侵入性中检测MGLUR1的改变。鉴于这一群体已经试图开发成功的宠物示踪剂，成功。因此，拟议的研究的目的是开发一个宠物示踪剂，以非侵入性监测体内与MGLUR1从大鼠到非人类灵长类动物的结合。我们提出了三个新的MGLUR1拮抗剂1、2和3（图2）作为宠物示踪剂开发的候选者，基于它们与MGLUR1的极好亲和力，足够的LOGP值，可容易进入大脑，可用的标签位点以及有希望的体内药理学数据。我们以良好的收率和特定活性完成了[11C] 1的合成。我们在验尸后人脑的幻灯片固定部分中的最初自显影研究导致[11C] 1与MGLUR1富含大脑区域的特异性结合（第4节）。因此，在此应用中，我们建议通过大鼠和狒狒研究来完成[11C] 1的表征，以便下一阶段的工作与在人类中的使用有关。 [11C] 1是一个有前途的铅示踪剂，其类似物2和3也被选为替代化合物。将对已知的MGLUR1拮抗剂JNJ16259685进行阻止研究，以获得大鼠和狒狒的特定结合。 [11C] 2和[11C] 3也将合成为替代配体，如果[11C] 1无法满足MGLUR1的特定PET示踪剂的标准，则依次研究。最佳宠物示踪剂将被确定用于建模研究并开发MAN中MGLUR1定量的方法。在第5节中给出了候选宠物示踪剂进行测试的选择标准，以及确定最成功的示踪剂的策略。在拟议的研究结束时，我们期望有PET示踪剂作为MGLUR1体内人类研究的潜在工具，并获得对MGLURUR的药物的占用。公共卫生相关性：代谢替型谷氨酸1受体（MGLUR1）参与了癫痫，缺血，焦虑，焦虑，抑郁和神经性疼痛的病理生理学，并且通过使用正电子发射断层扫描（PET），可以在体内无性级别和定量层次中测量受体系统中的变化。迄今为止，没有成功的宠物示踪剂用于MGLUR1的体内 /定量。因此，我们致力于为MGLUR1开发特定的宠物示踪剂，作为人类精神病研究和新药物开发的潜在工具