In vivo Probe for ionotropic glutamate signaling system: AMPA receptors

离子型谷氨酸信号系统体内探针：AMPA 受体

基本信息

批准号：
10584340
负责人：
Steven H Liang
金额：
$ 78.86万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-04 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10584340
关键词：
vivo Probe ionotropic glutamate signaling

项目摘要

Project Summary: We will develop the first subtype-selective positron emission tomography (PET) probe for α-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in the ionotropic glutamate system. Dysfunction of AMPAR is implicated in the physiopathology of neurological diseases such as schizophrenia, depression, epilepsy and Parkinson’s disease. Pharmacological modulation of AMPAR prevents excessive neuronal activation, representing an attractive therapeutic approach. As a non-invasive chemical probe, PET is capable of quantifying biochemical processes in vivo, and a suitable AMPAR PET probe would substantially improve our understanding of AMPAR-based ionotropic glutamate signaling under normal and disease conditions otherwise inaccessible by ex vivo (destructive) analysis. To date, no successful examples have been demonstrated to image AMPAR, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a PET probe that can fill this void, as the first translational AMPAR imaging tool. As pan AMPAR antagonists are often accompanied by debilitating adverse effects and have a very narrow therapeutic dosing window, one recent advance focuses on subtype-selective AMPAR antagonists via modulating transmembrane AMPA regulatory proteins (TARPs). The PI and his team have pioneered the development of the first subtype-selective AMPAR PET probe targeting AMPAR subunit TARP ɣ8, [11C]JNJ-486 at MGH. [11C]JNJ-486 showed high in vitro specific binding and target selectivity towards AMPAR TARP ɣ8 subunit, but was discontinued due to low brain penetration. Through our established HEK293 cell-based Ca2+ flux fluorescent assay, we identified a second generation chemical lead. This compound showed high potency and high subtype selectivity. An 11C- isotopologue was then synthesized and preliminary PET studies confirmed that we have overcome the two major obstacles for AMPAR probe development, namely: 1) reasonable brain uptake and 2) regional-specific uptake. Though this lead is a promising template for the development of new TARP ɣ8-targeted in vivo chemical tool, PET probes with improved potency & selectivity, and increased binding potentials (Bmax/Kd) are needed for optimal imaging and quantification of subtype-selective AMPAR in translational cross-species imaging studies. In this proposal, we will design and prepare a series of carefully chosen subtype-selective AMPAR inhibitors, label top candidates with 11C or 18F, and evaluate their ability to quantify AMPAR during drug challenges in rodents and nonhuman primates. The impact of this work is not only to develop the first potent and selective AMPAR PET probe for the study of disease-related biological processes, but also ultimately, to prepare this in vivo tool for potential clinical translation and monitor target response of AMPAR therapeutic agents in the brain. Relevance: This proposal has the potential to improve public health and help patients suffering from CNS disorders/neurodegenerative diseases through the discovery of neurotherapeutics using AMPAR PET probes.

项目概要：我们将开发第一个亚型选择性正电子发射断层扫描（PET）探针，用于α-氨基- 离子型谷氨酸系统中的 3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPAR)。 AMPAR 功能障碍与精神分裂症等神经系统疾病的病理生理学有关 AMPAR 的药理学调节可防止神经元过多。作为一种非侵入性化学探针，PET 能够进行激活。量化体内生化过程，合适的 AMPAR PET 探针将大大改善我们的研究了解正常和疾病条件下基于 AMPAR 的离子型谷氨酸信号传导迄今为止，还没有成功的实例证明可以通过离体（破坏性）分析来进行成像。 AMPAR，代表了我们体内研究该靶标的能力的重大缺陷，因此，我们建议开发一种可以填补这一空白的 PET 探针，作为第一个平移 AMPAR 成像工具。由于泛 AMPAR 拮抗剂常常伴随着使人衰弱的不良反应，并且作用范围非常狭窄。治疗剂量窗口，最近的一项进展侧重于通过调节亚型选择性 AMPAR 拮抗剂 PI 和他的团队率先开发了第一个跨膜 AMPA 调节蛋白 (TARP)。亚型选择性 AMPAR PET 探针靶向 MGH 的 AMPAR 亚基 TARP ɣ8、[11C]JNJ-486。对 AMPAR TARP ɣ8 亚基表现出高体外特异性结合和靶点选择性，但已停产由于脑渗透率低，通过我们建立的基于 HEK293 细胞的 Ca2+ 通量荧光测定，我们确定了一种该化合物显示出高效力和高亚型选择性。随后合成了同位素体，初步 PET 研究证实我们已经克服了两个主要问题 AMPAR 探针开发的障碍，即：1）合理的大脑摄取和 2）区域特定的摄取。尽管这一先导化合物是开发新型 TARP ɣ8 靶向体内化学工具的有前途的模板，但 PET 为实现最佳成像，需要具有更高效力和选择性以及更高结合电位 (Bmax/Kd) 的探针以及跨物种转化成像研究中亚型选择性 AMPAR 的量化。在这个提案中，我们将设计和制备一系列精心挑选的亚型选择性 AMPAR 抑制剂，标签具有 11C 或 18F 的顶级候选者，并评估他们在啮齿动物和药物挑战期间量化 AMPAR 的能力这项工作的影响不仅在于开发出第一个有效且选择性的 AMPAR PET 探针。用于研究与疾病相关的生物过程，但最终也是为潜在的临床准备这种体内工具翻译并监测 AMPAR 治疗药物在大脑中的目标反应。相关性：该提案有可能改善公共健康并帮助患有中枢神经系统疾病的患者通过使用 AMPAR PET 探针发现神经疗法来治疗疾病/神经退行性疾病。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Imaging of Transmembrane AMPA Receptor Regulatory Proteins by Positron Emission Tomography.

通过正电子发射断层扫描对跨膜 AMPA 受体调节蛋白进行成像。

DOI：
发表时间：
2022-07-14
期刊：
影响因子：
7.3
作者：
Yu, Qingzhen;Kumata, Katsushi;Rong, Jian;Chen, Zhen;Yamasaki, Tomoteru;Chen, Jiahui;Xiao, Zhiwei;Ishii, Hideki;Hiraishi, Atsuto;Shao, Tuo;Zhang, Yiding;Hu, Kuan;Xie, Lin;Fujinaga, Masayuki;Zhao, Chunyu;Mori, Wakana;Collier, Thomas;Haider
通讯作者：
Haider

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO.

用于神经炎症成像的小分子 PET 探针：TSPO 之外的挑战和机遇。

DOI：
发表时间：
2021-12-23
期刊：
影响因子：
7.3
作者：
Chen, Zhen;Haider, Ahmed;Chen, Jiahui;Xiao, Zhiwei;Gobbi, Luca;Honer, Michael;Grether, Uwe;Arnold, Steven E;Josephson, Lee;Liang, Steven H
通讯作者：
Liang, Steven H

Synthesis and evaluation of 6-(11C-methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein by PET.

6-(11C-甲基(4-(吡啶-2-基)噻唑-2-基)氨基)苯并[d]噻唑-2(3H)-一的合成和评估用于成像γ-8依赖性跨膜AMPA受体调节

DOI：
发表时间：
2020
期刊：
影响因子：
2.7
作者：
Yu, Qingzhen;Kumata, Katsushi;Li, Hua;Zhang, Yiding;Chen, Zhen;Zhang, Xiaofei;Shao, Tuo;Hatori, Akiko;Yamasaki, Tomoteru;Xie, Lin;Hu, Kuan;Wang, Gangqiang;Josephson, Lee;Sun, Shaofa;Zhang, Ming;Liang, Steven H
通讯作者：
Liang, Steven H

Radiosynthesis and preliminary evaluation of 11C-labeled 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[e] [1,2,4] thiadiazine 1,1-dioxide for PET imaging AMPA receptors.

11C标记的4-环丙基-7-(3-甲氧基苯氧基)-3,4-二氢-2H-苯并[e][1,2,4]噻二嗪1,1-二氧化物用于PET成像AMPA受体的放射合成和初步评价

DOI：
发表时间：
2020-03-19
期刊：
影响因子：
1.8
作者：
Chen, Jiahui;Gan, Jiefeng;Sun, Jiyun;Chen, Zhen;Fu, Hualong;Rong, Jian;Deng, Xiaoyun;Shang, Jingjie;Gong, Jian;Shao, Tuo;Collier, Lee;Wang, Lu;Xu, Hao;Liang, Steven H
通讯作者：
Liang, Steven H

Synthesis, pharmacology and preclinical evaluation of 11C-labeled 1,3-dihydro-2H-benzo[d]imidazole-2-ones for imaging γ8-dependent transmembrane AMPA receptor regulatory protein.

11C 标记的 1,3-二氢-2H-苯并[d]咪唑-2-酮的合成、药理学和临床前评估，用于成像 γ8 依赖性跨膜 AMPA 受体调节蛋白。

DOI：
10.1016/j.ejmech.2018.08.019
发表时间：
2018-09-05
期刊：
European journal of medicinal chemistry
影响因子：
6.7
作者：
Chen Z;Mori W;Zhang X;Yamasaki T;Dunn PJ;Zhang G;Fu H;Shao T;Zhang Y;Hatori A;Ma L;Fujinaga M;Xie L;Deng X;Li H;Yu Q;Rong J;Josephson L;Ma JA;Shao Y;Tomita S;Zhang MR;Liang SH
通讯作者：
Liang SH