Positive allosteric modulators as PET imaging ligands for mGluR4

作为 mGluR4 PET 成像配体的正变构调节剂

• 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
• 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' 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

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），每年产生60亿美元的健康成本。还有其他几种治疗费用极高的神经系统疾病，但在此背景下，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，可能介导超过50%的突触。最近的脑研究表明，代谢性谷氨酸受体（mGluRs）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激动剂和拮抗剂一直很困难，因为该受体家族成员的正位谷氨酸结合位点高度保守，并且占据结合口袋的药物载体的结构要求有限。缺乏特异性体内显像剂限制了个体mglur生理和病理作用的精确表征，从而阻碍了药物的开发。最近已经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，结合到位于七链跨膜结构域的变构结合位点上。我们之前已经合成并放射性标记了几种I组mGluR5的变构调节剂，并在临床前研究中将它们表征为PET成像配体。我们已经使用所有这些配体来研究小鼠，大鼠和灵长类动物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（pd样变性的最终生物标志物）的缺陷伴随着mGluR5的表达增强。mGlu5受体定位于突触后，提供谷氨酸的信息，并通过突触进行转运。然而，谷氨酸从神经元的突触前位置释放，使得突触前位置同样重要，如果不是更重要的话，可以用来研究神经传递。因此，定位于突触前的III组mGluR4受体是谷氨酸神经传递的重要参与者，特别是因为正变构调节剂可以增强mGluR4的正构激动剂来抑制GABA等神经递质的释放，从而平衡PD中直接和间接途径的神经传递。然而，目前还没有适合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，我们建议以2-吡啶酰胺衍生物为先导化合物合成mGluR4阳性变构调节剂的前体和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，这是任何体内成像方法都完全缺乏的。这一成功的研究成果将为尚未治疗的疾病的早期诊断和新的治疗方法开辟新的研究策略。