Positive allosteric modulators as PET imaging ligands for mGluR4

作为 mGluR4 PET 成像配体的正变构调节剂

基本信息

批准号：
8449493
负责人：
ANNA-LIISA BROWNELL
金额：
$ 55.08万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-03 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8449493
关键词：
Affinity Agonist Alzheimer&apos s Disease American Amino Acids Amyotrophic Lateral Sclerosis Animal Model Binding Binding Sites Biological Availability Biological Markers Blood Brain Brain imaging Characteristics Data Development Disease Disease model Drug Kinetics Dyskinetic syndrome Early Diagnosis Equilibrium Family Fluorine G-Protein-Coupled Receptors GRM5 gene Glutamate Receptor Glutamates Goals Health Care Costs Image Individual Kinetics Label Lead Levodopa Ligands Location Mediating Metabolism Metabotropic Glutamate Receptors Modeling Mus Neurons Neurotransmitters Parkinson Disease Pathway interactions Patients Physiological Plasma Positron Positron-Emission Tomography Primates Protein Binding Publications Publishing Radiolabeled Rattus Research Resolution Rodent Role Site Synapses System Techniques Testing Therapeutic Transformed Cell Line Transgenic Mice Transmembrane Domain Treatment Cost United States abnormal involuntary movement base brain research dopamine transporter drug development gamma-Aminobutyric Acid in vivo member metabotropic glutamate receptor 2 metabotropic glutamate receptor 4 mouse model nervous system disorder neural circuit neurotransmission neurotransmitter release novel pharmacophore preclinical study presynaptic public health relevance radiotracer receptor receptor function therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Half a million Americans suffer from Parkinson's disease (PD) incurring health cost of $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. Glutamate is the most abundant neurotransmitter in the brain and likely mediates more than 50% of all the synapses. The recent brain research has shown that metabotropic glutamate receptors (mGluRs) are involved in several neurological disorders including PD. Developing highly selective competitive agonists and antagonists for specific mGluR subtypes has been difficult, because of the high conservation of the orthosteric glutamate binding site across members of this receptor family and the restricted structural requirements for pharmacophores that occupy the binding pocket. Lack of specific in vivo imaging agents has limited the precise characterization of the physiological and pathological roles of individual mGluRs thus hampering drug development. Recently several non-competitive structurally diverse mGluR ligands have been published. These ligands, positive, negative and neutral modulators, bind to the allosteric binding sites located in the seven strand transmembrane domain. We have previously synthesized and radiolabeled several allosteric modulators for group I mGluR5 and characterized them as PET imaging ligands in preclinical studies. We have used all these ligands to investigate modulation of glutamatergic and dopaminergic receptor function in mouse, rat and primate PD models. We have shown that deficit in dopamine transporter function, the ultimate biomarker of PD-like degeneration, is accompanied with enhanced expression of mGluR5. mGlu5 receptors are localized postsynaptically providing information of glutamate, which is transported through the synapse. However, glutamate is released from the presynaptic site of the neuron, making presynaptic location equally if not more prominent to investigate neurotransmission. Thus, group III mGlu4 receptors localized presynaptically are important contributors for glutamate neurotransmission, especially since positive allosteric modulators can potentiate orthosteric agonist of mGluR4 to inhibit the release of neurotransmitters such as GABA and thus balance neurotransmission through direct and indirect pathways in PD. However, there is no in vivo imaging ligand available for mGluR4. Our ultimate goal is to synthesize positive allosteric compounds as specific PET imaging ligands for mGluR4. Precisely, we are proposing to synthesize precursors and develop radiolabeling techniques for mGluR4 positive allosteric modulators using 2-pyridylamide derivatives as lead compounds and investigate a role of presynaptic mGluR4 in glutamatergic neurotransmission. Our research effort is to develop imaging ligands for the receptor systems, what are totally lacking of any in vivo imaging approach. The successful accomplishment can open new research strategies for early diagnosis and novel therapies for the disorders, which do not have yet therapy.

描述（由申请人提供）： 50 万美国人患有帕金森病 (PD)，每年造成 60 亿美元的医疗费用。还有其他几种神经系统疾病的治疗成本极高，但在本文中，重点是与谷氨酸神经传递密切相关的疾病。谷氨酸是大脑中最丰富的神经递质，可能介导 50% 以上的突触。最近的大脑研究表明，代谢型谷氨酸受体 (mGluR) 与包括 PD 在内的多种神经系统疾病有关。开发针对特定 mGluR 亚型的高选择性竞争性激动剂和拮抗剂一直很困难，因为该受体家族成员之间的正位谷氨酸结合位点高度保守，并且占据结合袋的药效团的结构要求受到限制。缺乏特定的体内显像剂限制了单个 mGluR 生理和病理作用的精确表征，从而阻碍了药物开发。最近发表了几种非竞争性结构多样化的 mGluR 配体。这些配体（正、负和中性调节剂）与位于七链跨膜结构域的变构结合位点结合。我们之前已经合成并放射性标记了 I 组 mGluR5 的几种变构调节剂，并在临床前研究中将它们表征为 PET 成像配体。我们使用所有这些配体来研究小鼠、大鼠和灵长类 PD 模型中谷氨酸能和多巴胺能受体功能的调节。我们已经证明，多巴胺转运蛋白功能的缺陷（PD样变性的最终生物标志物）伴随着 mGluR5 表达的增强。 mGlu5 受体位于突触后，提供通过突触运输的谷氨酸信息。然而，谷氨酸从神经元的突触前位点释放，使得突触前位置在研究神经传递时同样突出（如果不是更突出的话）。因此，位于突触前的 III 族 mGlu4 受体是谷氨酸神经传递的重要贡献者，特别是因为正变构调节剂可以增强 mGluR4 的正位激动剂抑制 GABA 等神经递质的释放，从而通过直接和间接途径平衡 PD 中的神经传递。然而，没有可用于 mGluR4 的体内成像配体。我们的最终目标是合成正变构化合物作为 mGluR4 的特异性 PET 成像配体。准确地说，我们建议使用 2-吡啶酰胺衍生物作为先导化合物合成 mGluR4 正变构调节剂的前体并开发放射性标记技术，并研究突触前 mGluR4 在谷氨酸能神经传递中的作用。我们的研究工作是开发受体系统的成像配体，这是完全缺乏任何体内成像方法的。这一成功的成就可以为尚未有治疗方法的疾病的早期诊断和新疗法开辟新的研究策略。