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：
10224422
负责人：
ANNA-LIISA BROWNELL
金额：
$ 41.48万
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 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224422
关键词：
Academia Affect Affinity American 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 Models 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 Imaging ligands India Industry International Investigation Investigational New Drug Application Japan 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 Dose Unit 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 kinetic model 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：五十百万美国人患有帕金森氏病（PD），健康成本是一年60亿美元。还有其他几种神经系统疾病，治疗成本极高，但是在这种情况下，重点是与谷氨酸有密切联系的疾病神经传递。 MGLU4的突触前位置使其成为谷氨酸的重要贡献者神经传递自谷氨酸和多巴胺以来从神经元的突触前释放 MGLU4的激活可以抑制神经递质的释放，例如谷氨酸和GABA，因此通过PD中的直接和间接途径来平衡神经传递。最近的一些出版物提案特别是MGLU4作为包括PD在内的不同神经系统疾病的治疗靶点。我们有广泛的研究了阳性变构调节剂（PAM）作为MGLU4的PET成像配体。我们也调查了使用药物MRI方法的开发化合物的生物学活性。这些研究开辟了一种表征化合物并探索其用于治疗目的的可用性的新方法。我们基于MGLU4 PAM的两种不同的化学类型，已合成了32种不同的化合物。六个这些化合物的体内研究已作为MGLU4的PET成像配体的特征。主我们发达的配体中的限制是快速冲洗和代谢，即使具有约束力的亲和力已经体面了。我们还开发了特定的细胞系来表达MGLU4，并且细胞研究一直是配体表征的基础，以确定我们的结构亲密关系（SAR）实验性PAM并确定内源性谷氨酸与结合与变构调节剂的正常结合位点和亲和力。这些方法与经典方法在同一结合位点与内源配体竞争的经典方法。根据我们正在寻找开发尤其是氟-18的开拓性工作和全球兴趣标记了用于MGLU4的阳性变构成像配体，允许医疗应用和分布配体。确切地说，在AIM 1中，我们提议合成N-的两种F-18标记的铅化合物基于苯基吡啶酰胺和噻唑吡唑的MGLU4 PAMS研究其成像效率Bmax，选择性，大脑渗透，药代动力学，代谢稳定性和其他特性。在目标2中，我们将合成八个含氟N-苯基甲基酰胺衍生物和十二氟的新系列包含用于SAR分析的噻唑吡喃唑衍生物。这项工作将得到计算的支持化学。将选择两种最佳化合物作为MGLU4的PET成像配体。在 AIM 3我们将使用MGLU4基因敲除小鼠，大鼠和灵长类动物对这些配体进行体内表征最终目标的模型旨在验证人类研究的最佳化合物并获得IND批准。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fully Automated Radiosynthesis of [18F]mG4P027 for mGluR4 Imaging.

用于 mGluR4 成像的 [18F]mG4P027 全自动放射合成。

DOI：
10.1002/ird3.25
发表时间：
2023
期刊：
iRadiology
影响因子：
0
作者：
Moon,Sung-Hyun;ElFakhri,Georges;Zhang,Zhaoda;Brownell,Anna-Liisa;Wang,Junfeng
通讯作者：
Wang,Junfeng

A concise method for fully automated radiosyntheses of [18F]JNJ-46356479 and [18F]FITM via Cu-mediated 18F-fluorination of organoboranes.

一种通过有机硼烷的 Cu 介导的 18F 氟化来全自动放射合成 [18F]JNJ-46356479 和 [18F]FITM 的简明方法。

DOI：
10.1039/d0ra04943c
发表时间：
2020
期刊：
RSC advances
影响因子：
3.9
作者：
Yuan,Gengyang;Shoup,TimothyM;Moon,Sung-Hyun;Brownell,Anna-Liisa
通讯作者：
Brownell,Anna-Liisa

Transition Metal-Free Intermolecular C(sp2)-H Direct Amination of Furanones via a Redox Pathway.

DOI：
10.1021/acs.joc.8b02760
发表时间：
2019-01
期刊：
The Journal of organic chemistry
影响因子：
0
作者：
Q. Wei;Junfeng Wang;E. Akam;Dawei Yin;Z. Ge;T. Cheng;Xin Wang;A. Brownell;Runtao Li
通讯作者：
Q. Wei;Junfeng Wang;E. Akam;Dawei Yin;Z. Ge;T. Cheng;Xin Wang;A. Brownell;Runtao Li