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

• 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
• 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

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.

项目概述：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- 3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）在离子型谷氨酸系统。 AMPAR的功能障碍与神经系统疾病如精神分裂症的生理病理学有关， 抑郁症、癫痫症和帕金森病。AMPAR的药理学调节防止过度的神经元 激活，代表一种有吸引力的治疗方法。作为一种非侵入性化学探针，PET能够 定量体内生化过程，并且合适的AMPAR PET探针将大大改善我们的研究。 理解在正常和疾病条件下基于AMPAR的离子型谷氨酸信号传导 离体（破坏性）分析无法获得。到目前为止，还没有成功的例子被证明的形象 AMPAR，代表了我们在体内研究该靶点的能力的显著不足。因此，我们建议 开发一个PET探头，可以填补这一空白，作为第一个平移AMPAR成像工具。 由于泛AMPAR拮抗剂通常伴有使人衰弱的不良反应，并且具有非常窄的生物学效应。 治疗剂量窗口，一个最近的进展集中在亚型选择性AMPAR拮抗剂，通过调节 跨膜AMPA调节蛋白（TARP）。PI和他的团队率先开发了第一个 MGH靶向AMPAR亚基TARP β 8 [11 C]JNJ-486的亚型选择性AMPAR PET探针。[11 C]JNJ-486 显示出对AMPAR TARP β 8亚基的高体外特异性结合和靶向选择性，但已停止 因为大脑渗透率低通过我们建立的基于HEK 293细胞的Ca 2+通量荧光测定，我们鉴定了一种 第二代化学铅。该化合物显示出高效力和高亚型选择性。一个11 C- 然后合成了同位素体，初步的PET研究证实，我们已经克服了两个主要的 AMPAR探针开发的障碍，即：1）合理的脑摄取和2）区域特异性摄取。 虽然这一线索是一个有前途的模板，为发展新的TARP的tag 8靶向在体内的化学工具，PET 需要具有改进的效力和选择性以及增加的结合电位（Bmax/Kd）的探针以实现最佳成像 以及在翻译跨物种成像研究中亚型选择性AMPAR的定量。 在本研究中，我们将设计并制备一系列经过精心筛选的亚型选择性AMPAR抑制剂， 11 C或18F的最佳候选人，并评估其在啮齿动物药物挑战期间定量AMPAR的能力， 非人类灵长类动物这项工作的影响不仅是开发第一个有效的和选择性的AMPAR PET探针， 用于研究疾病相关的生物过程，但最终也是为了准备这种用于潜在临床的体内工具， 翻译和监测大脑中AMPAR治疗剂的靶向反应。 相关性：该提案有可能改善公共卫生并帮助CNS患者 通过使用AMPAR PET探针发现神经治疗剂来治疗疾病/神经退行性疾病。

项目成果

Small-animal PET study for noninvasive quantification of transmembrane AMPA receptor regulatory protein γ-8 (TARP γ-8) in the brain.

小动物 PET 研究，用于无创定量大脑中跨膜 AMPA 受体调节蛋白 γ-8 (TARP γ-8)。

• DOI: 10.1177/0271678x231152025
• 发表时间: 2023
• 期刊: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
• 作者: Yamasaki,Tomoteru;Ishii,Hideki;Hiraishi,Atsuto;Kumata,Katsushi;Wakizaka,Hidekatsu;Zhang,Yiding;Kurihara,Yusuke;Ogawa,Masanao;Nengaki,Nobuki;Chen,Jiahui;Li,Yinlong;Liang,Steven;Zhang,Ming-Rong
• 通讯作者: Zhang,Ming-Rong

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

• DOI: 10.1021/acs.jmedchem.2c00377
• 发表时间: 2022-07-14
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 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, Ahmed;Tomita, Susumu;Zhang, Ming-Rong;Liang, Steven
• 通讯作者: Liang, Steven

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: 10.1016/j.bmcl.2019.126879
• 发表时间: 2020
• 期刊: Bioorganic & medicinal chemistry letters
• 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-Rong;Liang,StevenH
• 通讯作者: Liang,StevenH

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

• DOI: 10.1021/acs.jmedchem.1c01571
• 发表时间: 2021-12-23
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 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.