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.

项目概要/摘要：本职业发展计划的目标是开发一个敏感的PET 用于mGluR 3体内成像的探针，这可能为阐明关键的生物化学特性提供有价值的见解。 阿尔茨海默病（AD）的发病机制，同时为我提供了一个很好的机会， 成长为独立的科学家。谷氨酸是脊椎动物中含量最丰富的兴奋性神经递质 中枢神经系统（CNS），其介导超过50%的所有突触。谷氨酸能 神经传递在各种脑功能中起重要作用，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， 导致突触改变、神经递质缺乏和认知障碍的复杂级联反应。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，并且它们中没有一个显示出显著的疾病改善活性。 我们对AD相关神经退行性变的病因学和病理生物学的理解仍然有限。的 研究表明，mGluR 3越来越多地与年龄相关的认知障碍有关， 刺激TGF-β的产生，挽救记忆缺陷并刺激α-分泌酶的活性。是 激活mGluR 3而不是mGluR 2诱导神经保护，而激活mGluR 2可能导致 神经毒性目前，PET成像在AD的诊断中具有越来越重要的作用。然而， PET在很大程度上取决于合适的PET放射性示踪剂的可用性。甚至，作为一个非常有前途的目标， 和其它CNS疾病，没有用于mGluR 3成像的PET配体。有巨大的需求， 和选择性成像配体，以验证药物靶点，并研究mGluR 3在生理和 病理过程。mGluR 3 PET示踪剂的潜在影响将主要用于研究潜在的 AD病理学和促进药物开发。 在这里，我们提出开发基于变构调节剂的mGluR 3选择性PET成像配体， 目的是评价已报道的先导化合物，进行SAR研究，优化先导化合物， 亲和性、选择性、代谢稳定性和其他药理学性质，放射性标记优化的 配体，并在动物模型中证明概念。具体来说，我们将开发氟-18标记的 PET示踪剂具有优化的药理学特性，用于选择性地在体内成像mGluR 3。我们将研究 mGluR 3在正常和病理条件下的表达、分布和功能，也使用AD- 小鼠模型。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， 药物和有机化学的PET成像探针的发展，并在 神经系统疾病的临床前研究，这可能会导致改善诊断，治疗选择， 监测疾病进展，同时在神经分子成像领域建立我。