Development of PET imaging probes for metabolic glutamate receptor 3 (mGLuR3)

代谢谷氨酸受体 3 (mGLuR3) PET 成像探针的开发

• 批准号: 10372080
• 负责人: JUNFENG WANG
• 金额: $ 15.07万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372080
• 关键词: Affinity; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Animal Model; Autoradiography; Binding Proteins; Biochemical; Biodistribution; Brain; Central Nervous System Diseases; Cholinesterase Inhibitors; Clinical; Cognition; Cognitive; Complex; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Drug Kinetics; Drug Targeting; Etiology; Evaluation; Event; Failure; Fluorine; Functional disorder; Glutamates; Goals; Image; Imaging ligands; Label; Lead; Learning; Ligands; Link; Mediating; Medical; Memantine; Memory; Memory impairment; Metabolic; Methods; Modeling; Molecular Probes; Monitor; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurology; Neurotransmitters; Organic Chemistry; Pathogenesis; Pathologic; Pathologic Processes; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiological; Physiological Processes; Play; Positron-Emission Tomography; Prevalence; Process; Production; Property; Radiolabeled; Rattus; Reporting; Research; Role; Scientist; Selection for Treatments; Series; Specificity; Synapses; Therapeutic; Tracer; Training; Transforming Growth Factor beta; Tritium; Work; age related cognitive disorder; alpha secretase; base; career development; design; drug development; glutamate receptor subunit 3; glutamatergic signaling; imaging probe; improved; in vivo; in vivo imaging; insight; lead optimization; metabotropic glutamate receptor 2; metabotropic glutamate receptor 3; molecular imaging; motor control; mouse model; nervous system disorder; neurodevelopment; neuroprotection; neurotoxicity; neurotransmission; non-invasive imaging; novel diagnostics; novel therapeutic intervention; preclinical study; radiotracer; response

Project Summary/Abstract: The goal of this career development proposal is to develop a sensitive PET probe for in vivo imaging of mGluR3, which might provide valuable insight to elucidate key biochemical mechanisms in the pathogenesis of Alzheimer's disease (AD) while providing me an excellent opportunity to grow as an independent scientist. Glutamate is the most abundant excitatory neurotransmitter in the vertebrate central nervous system (CNS), which mediates more than 50% of all synapses. The glutamatergic neurotransmission plays important roles in various brain functions, including motor control, learning and memory, cognition, and neural development. AD is a devastating neurodegenerative disorder that triggers a complex cascade leading to synaptic alterations, neurotransmitter deficiencies, and cognitive failure. Treatment of AD is the largest unmet need in neurology. Only four drugs (three cholinesterase inhibitors and memantine) are approved for the treatment of AD, and none of them has shown significant disease-modifying activity. Our understanding of the etiology and pathobiology of AD-related neurodegeneration remains limited. The studies show that mGluR3 is increasingly linked to age-related cognitive disorders, which are expected to stimulate the production of TGF-β, rescue memory deficits and to stimulate the activity of α-secretase. It is the activation of mGluR3 not mGluR2 to induce neuroprotection, while activation of mGluR2 may lead neurotoxicity. Presently, PET imaging has an increasing role in the diagnosis of AD. However, the potential of PET strongly depends on the availability of suitable PET radiotracers. Even, as a very promising target for AD and other CNS disorders, there is no PET ligand for imaging of mGluR3. There is tremendous need for specific and selective imaging ligands to verify the drug targets and to investigate mGluR3 in physiological and pathological processes. The potential impact of an mGluR3 PET tracer will be major to investigate underlying pathology of AD and enhance drug development. Here we propose to develop mGluR3-selective PET imaging ligands based on the allosteric modulators, with aims to evaluate the reported lead compounds, to carry out SAR study, to optimize the lead with respect to affinity, selectivity, metabolic stability and other pharmacological properties, to radiolabel the optimized ligands, and to demonstrate proof of concept in animal models. Specifically, we will develop fluorine-18 labeled PET tracers with optimized pharmacological properties for selectively imaging mGluR3 in vivo. We will study the expression, distribution and function of mGluR3 in normal and pathological conditions also using AD- mouse models. From the training perspective, the proposed work will allow me to extend my expertise in medicinal and organic chemistry to the development of PET imaging probes and characterize them in preclinical studies for neurological diseases, which could lead to improved diagnosis, treatment selection and monitoring disease progression while establishing me in the field of neurological molecular imaging.

项目摘要/摘要：这项职业发展计划的目标是开发敏感的宠物 MGLUR3体内成像的探针，这可能提供有价值的见解以阐明钥匙生化 阿尔茨海默氏病（AD）发病机理的机制，同时为我提供了一个绝佳的机会 成长为独立科学家。谷氨酸是脊椎动物中最丰富的兴奋性神经递质 中枢神经系统（CNS）介导了所有突触的50％以上。谷氨酸能 神经传递在各种大脑功能中都起着重要作用，包括运动控制，学习和 记忆，认知和神经发育。 AD是一种毁灭性的神经退行性疾病，可触发A 复杂的级联反应导致突触改变，神经递质缺陷和认知失败。治疗 AD是神经病学中最大的未满足需求。只有四种药物（三种胆碱酯酶抑制剂和美金刚） 被批准用于治疗AD，并且没有显示出明显的疾病改良活性。 我们对与广告相关神经变性的病因和病理生物学的理解仍然有限。这 研究表明，MGLUR3越来越多地与年龄相关的认知障碍联系在一起，预计这将是 刺激TGF-β的产生，拯救记忆定义并刺激α-分泌酶的活性。是 mglUR3非mglur2激活诱导神经保护，而Mglur2的激活可能会导致 神经毒性。目前，PET成像在AD的诊断中起着越来越多的作用。但是，潜力 PET很大程度上取决于合适的PET放射性示例的可用性。即使，作为广告的非常有希望的目标 和其他中枢神经系统疾病，没有用于MGLUR3成像的宠物配体。特定的非常需要 和选择性成像配体以验证药物靶标并研究物理和 MGLUR3 PET示踪剂的潜在影响将是研究基础的主要影响 AD的病理和增强药物开发。 在这里，我们建议基于变构调节剂，开发MGLUR3选择性PET成像配体， 旨在评估报告的铅化合物，进行SAR研究，以优化铅 具有选择性，选择性，代谢稳定性和其他药物特性，以辐射标记为优化 配体，并在动物模型中展示概念证明。具体而言，我们将开发标记为氟-18 具有优化药物特性的宠物示踪剂，用于在体内选择性成像MGLUR3。我们将学习 MGLUR3在正常和病理条件下的表达，分布和功能也使用AD- 鼠标模型。从培训的角度来看，拟议的工作将使我能够扩展我的专业知识 宠物成像问题的发展和有机化学，并将其描述 神经系统疾病的临床前研究，这可能会改善诊断，治疗选择和 监测疾病进展，同时在神经分子成像领域建立我。