Subtype-selective NMDA ligands for Alzheimer's Disease
阿尔茨海默病的亚型选择性 NMDA 配体
基本信息
- 批准号:10593906
- 负责人:
- 金额:$ 78.1万
- 依托单位:
- 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:2022-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:ABCB1 geneAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAutopsyAutoradiographyBindingBinding ProteinsBiochemical ProcessBiodistributionBiologicalBiological AssayBiological ProcessBlood specimenBrainClinicalDevelopmentDockingDoseEvaluationFunctional disorderGenerationsGlutamatesGoalsHumanImageImaging DeviceIn VitroKineticsKnowledgeLabelLeadLigandsLiver MicrosomesMetabolismMidbrain structureModelingMolecularMonitorN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeurodegenerative DisordersParentsPatientsPenetrationPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPlasmaPlasma ProteinsPontine structurePositron-Emission TomographyPublic HealthRadioactivityRadiolabeledReactionRodentScientific Advances and AccomplishmentsSeriesSiteSpecificityStandardizationSynaptic plasticitySystemTestingTherapeuticToxic effectTranslationsUnited StatesValidationWorkantagonistaspartate receptorbrain tissueclinical translationdesigndrug discoveryglutamatergic signalingimage translationimaging studyimprovedin vitro Assayin vivoin vivo evaluationlipophilicitynext generationnonhuman primatenovelpharmacokinetics and pharmacodynamicspharmacologicradioligandreceptorresponseuptakeylide
项目摘要
Project Summary: Dysfunction of GluN2B subunit in the N-Methyl-D-aspartic acid receptor (NMDAR) is implicated
in the physiopathology of neurodegenerative diseases such as Alzheimer’s disease (AD) and related dementia.
Pharmacological modulation of GluN2B subunit regulates synaptic plasticity and excitation, representing an attractive
therapeutic approach. PET is capable of quantifying biochemical processes in vivo, and a suitable GluN2B ligand
would substantially improve our understanding of GluN2B-based ionotropic glutamate signaling under
physiopathological conditions otherwise inaccessible by ex vivo (destructive) analysis. Quantification of GluN2B in
living brain by PET would provide the assessment of distribution, target engagement and dose occupancy of new
GluN2B-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image GluN2B for
human use, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to
develop a novel PET ligand that can overcome major drawbacks of previous attempts (low brain permeability / limited
target specificity / high lipophilicity), as the first translational imaging tool for drug discovery.
Our first generation GluN2B-targeted ligand, [18F]N2B-0518 showed excellent potency, target selectivity and high
specific binding, but was discontinued due to low brain penetration and fast metabolism in vivo. In our next generation,
we successfully identified a lead molecule, N2B-94, which showed high potency and selectivity towards GluN2B over
all other NMDAR subunits. An 11C-isotopologue of N2B-94 was synthesized and preliminary PET imaging studies
confirmed that we have overcome the major obstacles for GluN2B ligand development by achieving: 1) high brain
uptake; 2) high target specificity, as well as well-improved in vivo stability. Though N2B-94 is a promising lead
molecule, PET ligands with higher brain penetration, improved potency and selectivity with proper brain kinetics are
sought for translational cross-species imaging studies to achieve optimal quantification of GluN2B in the living brain.
On the basis that N2B-94 serves a validated hit for medicinal chemistry optimization, as specific goals, we will
design and prepare a series of GluN2B modulators amenable for labeling with 11C or 18F, and evaluate their ability to
quantify GluN2B activity and changes during drug challenge in rodents and nonhuman primates, as well as
autoradiography and biological validation in postmortem brain tissues from higher species. The impact of this work is
not only to develop the first potent and selective GluN2B PET ligand for the study of neurodegenerative disease-
related biological processes, but also ultimately, via PET imaging validation in higher species, to advance this ligand
for potential clinical translation and monitor target response of novel neurotherapeutics for neurodegenerative
diseases, including AD.
Relevance: This proposal has the potential to improve public health and help patients suffering from
neurodegenerative diseases, including AD, through the discovery of neurotherapeutics using GluN2B-selective
NMDAR PET ligands.
项目概述:涉及N-甲基-D-天冬氨酸受体(NMDAR)中GluN2B亚基的功能障碍
在神经退行性疾病如阿尔茨海默病(AD)和相关痴呆的生理病理学中。
GluN2B亚单位的药理学调节调节突触可塑性和兴奋,代表了一种有吸引力的
治疗方法PET能够量化体内的生物化学过程,并且合适的GluN2B配体
将大大提高我们对GluN2B为基础的离子型谷氨酸信号的理解,
病理生理状况,否则无法通过离体(破坏性)分析获得。GluN2B的定量
通过PET的活体脑将提供新的放射性核素的分布、靶向接合和剂量占用的评估。
GluN2B靶向神经疗法。迄今为止,还没有成功的例子被证明可以对GluN2B进行成像,
人类使用,代表我们在体内研究该靶点的能力的显著不足。因此,我们建议
开发一种新的PET配体,可以克服以前尝试的主要缺点(低脑渗透性/有限
靶特异性/高亲脂性),作为药物发现的第一个翻译成像工具。
我们的第一代GluN2B靶向配体,[18F] N2B-0518显示出优异的效力、靶向选择性和高选择性。
特异性结合,但由于脑渗透性低和体内代谢快而停止。在我们的下一代,
我们成功地鉴定了一个先导分子N2B-94,它对GluN2B表现出高效力和选择性,
所有其他NMDAR亚单位。合成N2B-94的11C-同位素体,并进行初步PET成像研究。
证实了我们已经克服了GluN2B配体开发的主要障碍,实现了:1)高脑
摄取; 2)高靶特异性,以及良好改善的体内稳定性。虽然N2B-94是一个有希望的线索,
分子,PET配体具有更高的脑渗透性,改善的效力和选择性以及适当的脑动力学,
寻求翻译跨物种成像研究,以实现活脑中GluN2B的最佳定量。
基于N2B-94为药物化学优化提供了经验证的命中,作为具体目标,我们将
设计并制备一系列适合用11C或18F标记的GluN2B调节剂,并评估它们的能力,
定量啮齿类动物和非人灵长类动物在药物激发期间的GluN2B活性和变化,以及
放射自显影和生物学验证在死后的脑组织从高等物种。这项工作的影响是
不仅开发了第一个有效的和选择性的GluN2B PET配体用于神经退行性疾病的研究,
相关的生物过程,但最终,通过PET成像验证在更高的物种,以推进这种配体
用于神经退行性疾病新型神经疗法的潜在临床转化和监测目标反应
疾病,包括AD。
相关性:该提案有可能改善公共卫生,帮助患有糖尿病的患者。
神经退行性疾病,包括AD,通过发现使用GluN2B选择性
NMDAR PET配体。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Steven H Liang其他文献
Ru-Photoredox-Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids through N-(acyloxy)phthalimide
Ru-光氧化还原催化 N-(酰氧基)邻苯二甲酰亚胺对脂肪族羧酸进行脱羧氧化
- DOI:
10.1021/acs.orglett.8b01885 - 发表时间:
2018 - 期刊:
- 影响因子:5.2
- 作者:
Chao Zheng;Yuting Wang;Yangrui Xu;Zhen Chen;Guangying Chen;Steven H Liang - 通讯作者:
Steven H Liang
Steven H Liang的其他文献
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{{ truncateString('Steven H Liang', 18)}}的其他基金
Subtype-Selective Metabotropic Glutamate Receptor PET Ligands
亚型选择性代谢型谷氨酸受体 PET 配体
- 批准号:
10576674 - 财政年份:2023
- 资助金额:
$ 78.1万 - 项目类别:
Glycogen synthase kinase 3 ligand discovery for Alzheimer’s disease
糖原合成酶激酶 3 配体发现治疗阿尔茨海默病
- 批准号:
10637434 - 财政年份:2023
- 资助金额:
$ 78.1万 - 项目类别:
Subtype-selective phosphodiesterase PET ligands
亚型选择性磷酸二酯酶 PET 配体
- 批准号:
10568308 - 财政年份:2023
- 资助金额:
$ 78.1万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 78.1万 - 项目类别:
Subtype-selective NMDA ligands for Alzheimer's Disease
阿尔茨海默病的亚型选择性 NMDA 配体
- 批准号:
10355691 - 财政年份:2022
- 资助金额:
$ 78.1万 - 项目类别:
PET ligand discovery for arginine vasopressin
精氨酸加压素的 PET 配体发现
- 批准号:
10641669 - 财政年份:2022
- 资助金额:
$ 78.1万 - 项目类别:
PET imaging of ionotropic glutamate receptor signaling in Alzheimer's disease
阿尔茨海默病中离子型谷氨酸受体信号传导的 PET 成像
- 批准号:
10574694 - 财政年份:2022
- 资助金额:
$ 78.1万 - 项目类别:
PET ligand discovery for arginine vasopressin
精氨酸加压素的 PET 配体发现
- 批准号:
10356395 - 财政年份:2022
- 资助金额:
$ 78.1万 - 项目类别:
PET Imaging for neuroinflammation in Alzheimer's disease
阿尔茨海默病神经炎症的 PET 成像
- 批准号:
10653556 - 财政年份:2022
- 资助金额:
$ 78.1万 - 项目类别:
PET imaging for neuroimmune function in Alzheimer's disease
PET 成像研究阿尔茨海默病的神经免疫功能
- 批准号:
10474697 - 财政年份:2022
- 资助金额:
$ 78.1万 - 项目类别: