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:10355691
- 负责人:
- 金额:$ 78.22万
- 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 PreparationsPharmacologyPlasmaPlasma ProteinsPontine structurePositron-Emission TomographyPublic HealthRadioactivityRadiolabeledReactionRodentScientific Advances and AccomplishmentsSeriesSiteSpecificityStandardizationSynaptic plasticitySystemTestingTherapeuticToxic effectTranslationsUnited StatesValidationWorkantagonistaspartate receptorbasebrain tissueclinical translationdesigndrug discoveryglutamatergic signalingimaging studyimprovedin vitro Assayin vivoin vivo evaluationlipophilicitynext generationnonhuman primatenovelpharmacokinetics and pharmacodynamicsradioligandreceptorresponseuptakeylide
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.
项目摘要:与n -甲基- d -天冬氨酸受体(NMDAR) GluN2B亚基功能障碍有关
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:
$ 78.22万 - 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:
$ 78.22万 - 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:
$ 78.22万 - 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:
10593906 - 财政年份:2022
- 资助金额:
$ 78.22万 - 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:
$ 78.22万 - 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:
$ 78.22万 - 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:
$ 78.22万 - 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:
$ 78.22万 - 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:
$ 78.22万 - 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:
$ 78.22万 - 项目类别: