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

基本信息

批准号：
10608944
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608944
关键词：
Affinity Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Animal Model Autoradiography Binding Proteins Biochemical Biodistribution Brain Central Nervous System 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 Neurodegenerative Disorders Neurologic Neurology Neurotransmitters Organic Chemistry Pathogenesis Pathologic Pathologic Processes Penetration Pharmaceutical Chemistry Pharmaceutical Preparations 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 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 pharmacologic preclinical study radiotracer response

项目摘要

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：本职业发展提案的目标是培养敏感的 PET 用于 mGluR3 体内成像的探针，这可能为阐明关键生化提供有价值的见解阿尔茨海默病（AD）发病机制的同时为我提供了一个绝佳的机会成长为一名独立科学家。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 50% 以上的突触。神经传递在各种大脑功能中发挥着重要作用，包括运动控制、学习和 AD 是一种破坏性的神经退行性疾病，会引发记忆、认知和神经发育。复杂的级联反应导致突触改变、神经递质缺乏和认知障碍。 AD 的最大未满足需求只有四种药物（三种胆碱酯酶抑制剂和美金刚）。已被批准用于治疗 AD，但它们均未显示出显着的疾病缓解活性。我们对 AD 相关神经变性的病因学和病理学的了解仍然有限。研究表明，mGluR3 与年龄相关的认知障碍的关系越来越密切，预计这会刺激 TGF-β 的产生，挽救记忆缺陷并刺激 α-分泌酶的活性。激活 mGluR3 而不是 mGluR2 来诱导神经保护，而激活 mGluR2 可能会导致目前，PET 成像在 AD 诊断中的作用越来越大。 PET 强烈依赖于合适的 PET 放射性示踪剂的可用性，甚至作为 AD 的一个非常有前途的目标。和其他中枢神经系统疾病一样，没有用于 mGluR3 成像的 PET 配体，因此非常需要特异性的配体。和选择性成像配体以验证药物靶点并研究 mGluR3 的生理和功能 mGluR3 PET 示踪剂的潜在影响对于研究潜在的病理过程至关重要。 AD 的病理学并加强药物开发。在这里，我们建议开发基于变构调节剂的 mGluR3 选择性 PET 成像配体，目的是评估已报道的先导化合物，进行SAR研究，优化先导化合物亲和力、选择性、代谢稳定性和其他药理学特性，以放射性标记优化的具体来说，我们将开发氟18标记我们将研究具有优化药理学特性的 PET 示踪剂，用于选择性地对 mGluR3 进行体内成像。 mGluR3 在正常和病理条件下的表达、分布和功能也使用 AD- 从训练的角度来看，拟议的工作将使我能够扩展我的专业知识。药物和有机化学到 PET 成像探针的开发及其表征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，同时奠定我在神经分子成像领域的地位。