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: 8141049
• 负责人: ANNA-LIISA BROWNELL
• 金额: $ 56万
• 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/8141049
• 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; 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. PUBLIC HEALTH RELEVANCE: Six million people have Parkinson's disease worldwide, half a million of them in the United States incurring health cost of $6 billion in a year. Mostly used treatment in PD is pharmacological therapy with L-dopa. However after 5 yrs use of L-dopa more than 50 % of the patients will develop abnormal involuntary movement called L-dopa induced dyskinesia (LID). It was shown in preliminary studies that mGluRs, especially mGluR4 has inhibitory effect on the development of LID. There is no in vivo imaging ligand for mGluR4. Our goal is to develop PET imaging ligands for mGluR4 and investigate a role of mGluR4 in glutamatergic neurotransmission.

描述（由申请人提供）：50万美国人患有帕金森氏病（PD），一年的健康成本为60亿美元。还有其他几种神经系统疾病的治疗成本极高，但是在这种情况下，重点是与谷氨酸神经传递有密切联系的疾病。谷氨酸是大脑中最丰富的神经递质，可能会介导所有突触的50％以上。最近的大脑研究表明，代谢型谷氨酸受体（MGLURS）参与包括PD在内的几种神经系统疾病。由于该受体家族成员之间的正正确性谷氨酸结合位点的高度保存以及占据结合口袋的药物团的结构要求，为特定的MGLUR亚型开发高度选择性的竞争激动剂和拮抗剂非常困难。缺乏特定的体内成像剂限制了单个mglurs的生理和病理作用的精确表征，从而妨碍了药物的发展。最近，已经发表了几种非竞争性的结构多样性的MGLUR配体。这些配体（正，负和中性调节剂）与位于七个链跨膜结构域中的变构结合位点结合。我们以前已经合成了I组MGLUR5的几个变构调节剂并放射标记，并将其表征为临床前研究中的PET成像配体。我们已经使用所有这些配体研究了小鼠，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。我们已经表明，多巴胺转运蛋白转运蛋白函数（PD样变性的最终生物标志物）伴随着MGLUR5的增强表达。 MGLU5受体是局部突触的局部提供的，可提供谷氨酸的信息，该信息是通过突触传输的。但是，谷氨酸是从神经元的突触前部位释放出来的，这使得调查神经传递的突触前位置同样突出。因此，III组MGLU4受体在突触前定位是谷氨酸神经传递的重要因素，尤其是因为阳性变构调节调节剂可以增强MGLUR4的正构性激动剂，以抑制神经递质的释放，从而释放GABA（例如GABA），从而通过直接和独立路线平衡神经透射。但是，没有可用于MGLUR4的体内成像配体。我们的最终目标是将阳性变构化合物作为MGLUR4的特定PET成像配体。确切地说，我们建议使用2-吡啶基胺衍生物作为铅化合物合成前体，并开发用于MGLUR4阳性变构调节剂的放射性标记技术，并研究谷氨酸神经传输中突触前MGLUR4的作用。我们的研究工作是为受体系统开发成像配体，完全缺乏任何体内成像方法。成功的成就可以为早期诊断和尚无治疗的疾病的新疗法开辟新的研究策略。 公共卫生相关性：全世界有600万人患有帕金森氏病，其中有50万人在美国造成的健康成本为60亿美元。 PD中主要使用的是L-DOPA的药理学治疗。但是，使用5年使用L-DOPA后，超过50％的患者将发展出异常的非自愿运动，称为L-DOPA诱导的运动障碍（LID）。在初步研究中表明，mglurs，尤其是mglur4对盖子的发展具有抑制作用。 Mglur4没有体内成像配体。我们的目标是开发用于MGLUR4的PET成像配体，并研究MGLUR4在谷氨酸能神经传递中的作用。