Simultaneous PET/phMR studies on interplay of mGlu/dopamine receptors in PD-like neurodegeneration

同步 PET/phMR 研究 mGlu/多巴胺受体在 PD 样神经变性中的相互作用

• 批准号: 10518778
• 负责人: ANNA-LIISA BROWNELL
• 金额: $ 68.97万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518778
• 关键词: Age; Agonist; Amphetamines; Animal Disease Models; Area; Basal Ganglia; Behavioral; Brain; Brain region; Clinical Trials; Cognitive; Complex; Corpus striatum structure; Data; Denervation; Diagnostic; Disease; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug Addiction; Drug Design; Drug Targeting; Drug abuse; Epilepsy; Experimental Animal Model; Failure; Female; Future; GRM5 gene; Glutamates; Image; Imaging ligands; Individual; Lesion; Ligands; Limbic System; Magnetic Resonance Imaging; Maps; Measures; Mediating; Metabotropic Glutamate Receptors; Modeling; Mood Disorders; Nerve Degeneration; Neurobiology; Neuronal Plasticity; Neurotransmitters; Oxidopamine; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Positron-Emission Tomography; Presynaptic Receptors; Process; Rattus; Regulation; Role; Schizophrenia; Signal Transduction; Specificity; Sprague-Dawley Rats; Support System; Symptoms; Synapses; Synaptic Cleft; Synaptic plasticity; System; Techniques; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tropanes; Up-Regulation; addiction; alpha synuclein; antagonist; base; behavioral study; benzonitrile; brain circuitry; brain research; cerebral blood volume; chronic pain; density; design; diagnostic tool; disease diagnostic; disorder prevention; dopamine transporter; drug development; imaging study; in vivo imaging; instrumentation; male; metabotropic glutamate receptor 4; neurochemistry; neurotoxicity; neurotransmission; positive allosteric modulator; postsynaptic; presynaptic; pyridine; radioligand; real-time images; receptor; receptor function; response; sensor; serial imaging; side effect; theories; time use; transmission process

ABSTRACT Research of the brain receptor functions holds a promise to provide better diagnostic tools and drugs that could be tailored for the individual needs, thereby eliminating or reducing side effects and even providing a way for prevention of diseases. Increasing understanding of receptor functions is revealing complex and dynamic interactions between neurotransmitter systems. In the basal ganglia, dopamine (DA) regulation of glutamate (Glu) neurotransmission is complex and the loss of DA-mediated inhibition in the striatum f. ex. in Parkinson disease (PD) results in an imbalance of other neurotransmitters, mostly excitatory. Metabotropic glutamate receptors (mGluR)s are activated when there is excess Glu in the synaptic cleft and therefore act as sensors and modulators when or where Glu transmission is enhanced. This functional specificity makes them attractive pharmacological targets. The prevalent localization of mGluRs in the striatum and limbic system supports their role in modulating DA and Glu-dependent signaling and synaptic plasticity within the basal ganglia cortico-subcortical loops. A recent failure of the first clinical trial focusing on agonizing of mGluR4 function inspired this project to investigate the fundamentals of dopaminergic and glutamatergic interplay in PD-like neurodegeneration. We have developed high level imaging instrumentation and techniques as well as unique ligands to conduct quantitative in vivo imaging studies of dopaminergic and glutamatergic neurofunction. We have earlier developed radioligands for PET imaging of dopamine transporters as well as pharmacological MRI (phMRI) to investigate dopamine release. Recently, we have developed allosteric modulators as PET imaging ligands for mGluR4 (presynaptic receptor) and mGluR5 (postsynaptic receptor) and characterized them in experimental animal models. Now we are proposing to combine the phMR imaging of amphetamine induced dopamine release or excessive synaptic glutamate concentration induced by agonizing mGluR4 with mG4P027 (N-(4-chloro-3-((fluoromethyl-d2)thio)phenyl)picolinamide) or antagonizing mGluR5 function with MTEP ((2-methyl-1,3-thiazo-4-yl)ethynyl pyridine) with simultaneous PET imaging of mGluR4, mGluR5 and dopamine D2 receptor function to investigate degeneration induced modulation of dopaminergic and glutamatergic neurotransmission using α- synuclein rat model of PD and its additional 6-OHDA lesioned counterpart (combination model). Real time imaging of receptor modulation will challenge the present theories of signaling and synaptic plasticity during degenerative processes. The results of this receptor modulation can be readily utilized in the drug development for dopamine-glutamate regulation related disorder, like Parkinson’s disease, schizophrenia or drug addiction.

抽象的 大脑受体功能的研究有望提供更好的诊断工具和药物 可以根据个人需求进行定制，从而消除或减少副作用，甚至提供 预防疾病的一种方法。加深对受体功能的了解揭示了复杂的 以及神经递质系统之间的动态相互作用。在基底神经节中，多巴胺 (DA) 谷氨酸（Glu）神经传递的调节是复杂的，DA介导的抑制作用的丧失 纹状体 f.前任。帕金森病 (PD) 会导致其他神经递质失衡，主要是 令人兴奋的。当体内 Glu 过多时，代谢型谷氨酸受体 (mGluR) 就会被激活。 突触间隙，因此在 Glu 传输增强时或处充当传感器和调制器。 这种功能特异性使它们成为有吸引力的药理学靶点。普遍的本地化 纹状体和边缘系统中的 mGluR 支持其在调节 DA 和 Glu 依赖性中的作用 基底节皮质-皮质下环内的信号传导和突触可塑性。最近的一次失败 第一个关注 mGluR4 功能的痛苦的临床试验激发了这个项目的研究 PD 样神经变性中多巴胺能和谷氨酸能相互作用的基本原理。我们有 开发了高水平成像仪器和技术以及独特的配体来进行 多巴胺能和谷氨酸能神经功能的定量体内成像研究。我们早先有 开发了用于多巴胺转运蛋白 PET 成像以及药理学 MRI 的放射性配体 （phMRI）研究多巴胺的释放。最近，我们开发了变构调节剂PET mGluR4（突触前受体）和 mGluR5（突触后受体）的成像配体 在实验动物模型中对它们进行了表征。现在我们建议将 phMR 结合起来 安非他明诱导的多巴胺释放或突触谷氨酸浓度过高的成像 通过用 mG4P027（N-(4-氯-3-((氟甲基-d2)硫基)苯基)吡啶酰胺）激动 mGluR4 诱导 或用 MTEP（(2-甲基-1,3-噻唑-4-基）乙炔基吡啶）拮抗 mGluR5 功能 mGluR4、mGluR5 和多巴胺 D2 受体功能的同步 PET 成像以研究 使用 α- 退化诱导多巴胺能和谷氨酸能神经传递的调节 PD 及其附加 6-OHDA 损伤对应物的突触核蛋白大鼠模型（组合模型）。真实的 受体调节的时间成像将挑战现有的信号传导和突触理论 退化过程中的可塑性。这种受体调节的结果可以很容易地用于 多巴胺谷氨酸调节相关疾病（如帕金森病）的药物开发， 精神分裂症或毒瘾。