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Positive Allosteric Modulators as PET Imaging Ligans for mGluR4

作为 mGluR4 PET 成像配体的正变构调节剂

基本信息

批准号：
9358362
负责人：
ANNA-LIISA BROWNELL
金额：
$ 64.56万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9358362
关键词：
Academia Affect Affinity American Anti-HIV Agents Antiparkinson Agents Binding Binding Proteins Binding Sites Biological Biological Availability Blood Blood Volume Brain Brain imaging Cell Line Cells Central Nervous System Diseases China Clinical Trials Computer Simulation Data Development Diagnostic Disease Dopamine Dose Drug Compounding Drug Design Drug Kinetics Equilibrium Evaluation Fluorine Future GRM5 gene Germany Glutamates Goals Health Care Costs Human Image India Industry International Investigation Investigational New Drug Application Japan Kinetics Knockout Mice Label Lead Letters Ligands Location Magnetic Resonance Imaging Medical Metabolic Metabolism Modeling Neurodegenerative Disorders Neurons Parkinson Disease Pathology Pathway interactions Penetration Pharmaceutical Preparations Pharmacology Physiological Plasma Positron-Emission Tomography Primates Process Property Publications Publishing Radiation Radiolabeled Rattus Research Resolution Series Site Structure Synapses System Testing Therapeutic Therapeutic Uses Time Toxicology Tracer Transformed Cell Line Treatment Cost Work base computational chemistry cross reactivity drug development drug discovery gamma-Aminobutyric Acid imaging study in vivo in vivo imaging interest metabotropic glutamate receptor 4 nervous system disorder neural circuit neurotransmission neurotransmitter release novel therapeutic intervention positive allosteric modulator pre-clinical presynaptic presynaptic neurons radiotracer receptor receptor function theories therapeutic target usability

项目摘要

ABSTRACT: Half a million Americans suffer from Parkinson’s disease (PD) and the incurring health cost is $6 billion in a year. There are several other neurological disorders with extremely high cost for treatment, but in this context the focus is on the disorders, which have strong connection to glutamate neurotransmission. Presynaptic location of mGlu4 makes them important contributors for glutamate neurotransmission since glutamate as well as dopamine is released from the presynaptic site of the neuron and activation of mGlu4 can inhibit the release of neurotransmitters such as glutamate and GABA and thus balance neurotransmission through direct and indirect pathways in PD. Several recent publications propose especially mGlu4 as therapeutic target for different neurological diseases including PD. We have extensively investigated positive allosteric modulators (PAMs) as PET imaging ligands for mGlu4. We investigated also biological activity of the developed compounds using pharmacological MRI approaches. These studies opened a new way to characterize compounds and explore their usability for therapeutic purposes. We have synthetized 32 different compounds based on two different chemo-types of the mGlu4 PAMs. Six of these compounds have been characterized with in vivo studies as PET imaging ligands for mGlu4. The main limitation in our developed ligands has been fast washout and metabolism, even though binding affinities have been decent. We also developed specific cell lines to express mGlu4 and the cell studies have been fundamental in ligand characterization to determine the structure-affinity relationship (SAR) of our experimental PAMs and determine co-operative relationship between endogenous glutamate binding to orthosteric binding sites and affinity of allosteric modulators. These approaches are radically different from classical approach in which orthosteric ligands compete with endogenous ligands at the same binding site. Based on the pioneering work and worldwide interest we are looking for to develop especially fluorine-18 labeled positive allosteric imaging ligands for mGlu4 allowing medical applications and distribution of the ligands. Precisely, in Aim 1 we are proposing to synthesize two F-18 labeled lead compounds from the N- phenylpicolinamide- and thiazolopyrazole-based mGlu4 PAMs to study their imaging efficacy, Bmax, selectivity, brain penetration, pharmacokinetics, metabolic stability and other properties. In Aim 2 we will synthesize new series of eight fluorine-containing N-phenylpicolinamide derivatives and twelve fluorine- containing thiazolopyrazole derivatives for SAR analyses. This effort will be supported by computational chemistry. Two best compounds will be selected for the development as PET imaging ligands for mGlu4. In Aim 3 we will conduct in vivo characterization of these ligands using mGlu4 knockout mice, rat and primate models with an ultimate goal to validate the best compound for human studies and obtain IND approval.

摘要：美国有50万人患有帕金森病，其医疗费用是一年60亿还有其他几种治疗费用极高的神经系统疾病，但在这种情况下，重点是与谷氨酸盐密切相关的疾病，神经传递mGlu 4的突触前位置使其成为谷氨酸的重要贡献者由于谷氨酸和多巴胺从神经元的突触前部位释放， mGlu 4的激活可以抑制神经递质如谷氨酸和GABA的释放，通过直接和间接途径平衡PD中的神经传递。最近的一些出版物提出，特别是mGlu 4作为包括PD在内的不同神经系统疾病的治疗靶点。我们广泛研究了正变构调节剂（PAM）作为mGlu 4的PET成像配体。我们还调查了使用药理学MRI方法的开发的化合物的生物活性。这些研究开辟了表征化合物并探索其用于治疗目的的可用性的新途径。我们基于mGlu 4 PAM的两种不同化学类型合成了32种不同的化合物。六这些化合物已经通过体内研究表征为mGlu 4的PET成像配体。主要我们开发的配体的限制是快速洗脱和代谢，即使结合亲和力都很得体我们还开发了表达mGlu 4的特异性细胞系，细胞研究已被证实。配体表征的基础，以确定我们的结构-亲和关系（SAR）实验性PAM，并确定内源性谷氨酸结合与正构结合位点和别构调节剂的亲和力。这些方法完全不同于经典的方法，其中正构配体与内源性配体在相同的结合位点竞争。基于开创性的工作和世界范围内的兴趣，我们正在寻找开发特别是氟-18 标记的mGlu 4的正变构成像配体，其允许医疗应用和分布，配体。准确地说，在目标1中，我们提出从N-甲基-N- 基于苯基吡啶酰胺和噻唑并吡唑的mGlu 4 PAM，以研究其成像功效，Bmax，选择性、脑渗透性、药代动力学、代谢稳定性和其它性质。在目标2中，合成了新系列八种含氟N-苯基吡啶酰胺衍生物和十二种含氟含有噻唑并吡唑衍生物，用于SAR分析。这一努力将得到计算支持。化学.将选择两种最佳化合物作为mGlu 4的PET成像配体用于开发。在目的3我们将使用mGlu 4敲除小鼠、大鼠和灵长类动物进行这些配体的体内表征该模型的最终目标是验证用于人体研究的最佳化合物并获得IND批准。