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
基本信息
- 批准号:10637434
- 负责人:
- 金额:$ 232.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:ABCB1 geneABCG2 geneAbeta synthesisAffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAutopsyAutoradiographyBindingBinding ProteinsBiochemical ProcessBiodistributionBiologicalBiological AssayBiological ProcessBlood specimenBrainCellsCharacteristicsChemicalsChemistryClinicalDevelopmentDockingDoseEnzymesEvaluationFamilyFunctional disorderGenerationsGlycogen Synthase Kinase 3GoalsHumanImageImaging DeviceIn VitroInflammationKineticsKnockout MiceKnowledgeLabelLeadLibrariesLigandsLiver MicrosomesMediatingMolecularMonitorNational Institute of Mental HealthNeurodegenerative DisordersNeuroimmunePenetrationPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPhosphotransferasesPlasmaPlasma ProteinsPositron-Emission TomographyRadiolabeledResearchRodentRoleSafetyScientific Advances and AccomplishmentsSelection CriteriaSignal PathwaySiteSpecificityTestingTherapeuticToxic effectTranslationsUnited StatesValidationWorkbrain tissueclinical translationdesigndrug discoveryimage translationimaging studyimprovedin vivoin vivo evaluationkinetic modellipophilicitymouse modelneurogenesisnonhuman primatenovelpharmacokinetics and pharmacodynamicspharmacologicradioligandresponsesample fixationsynaptic functiontau-1uptake
项目摘要
Project Summary. Glycogen synthase kinase 3 (GSK3) is considered a key player in the pathophysiology of
Alzheimer’s disease (AD) since dysregulation of this enzyme influences all the major AD hallmarks, including tau
phosphorylation, amyloid-β production, neurogenesis, inflammation and synaptic function. Therefore pharmacological
modulation of GSK3 represents an attractive therapeutic approach for the treatment of AD. Positron emission
tomography (PET) is capable of quantifying biochemical processes in vivo, and a suitable GSK3 ligand would
substantially improve our understanding of GSK3-mediated signaling pathway under different pathophysiological AD
conditions, otherwise inaccessible by ex vivo (destructive) analysis. Quantification of GSK3 in living brain by PET
would provide the assessment of distribution, target engagement and dose occupancy of new GSK3-targeted
neurotherapeutics. To date, no successful examples have been demonstrated to image GSK3 in human for drug
discovery and clinical 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 fill this void, as the first translational imaging tool.
We are the first groups to develop GSK3-specific ligands in cross-species PET studies, including the first selective
ligand [11C]PF-367. However, this ligand was discontinued due to low-to-moderate brain uptake and marginal binding
specificity in vivo. In our 2nd generation, we identified a lead molecule, GSK3-817, which showed high binding affinity
and excellent selectivity. An 18F-isotopologue of GSK3-817 was synthesized and preliminary PET imaging studies
confirmed that we have overcome two major obstacles for GSK3-specific kinase ligand development by achieving: 1)
substantially-improved brain penetration (≥1 SUV brain uptake) and 2) reasonable target specificity. Though GSK3-
817 is a promising lead molecule for the development of new GSK3-targeted PET ligands, further optimization for
improved binding specificity and proper brain kinetics are sought for translational cross-species (rodents and
nonhuman primates) imaging studies to achieve optimal GSK3 quantification for drug discovery and clinical translation
for AD patients.
On the basis that GSK3-817 serves a validated lead for medicinal chemistry optimization, as specific goals, we
will design and prepare a focused library of GSK3-specific modulators amenable for labeling with 11C or 18F (preferred),
and evaluate their ability to quantify GSK3 expression and changes during drug challenge in rodents and nonhuman
primates, as well as autoradiography and biological validation in postmortem human brain tissues. The impact of this
work is not only to develop the first successful highly-specific GSK3 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.
项目总结。糖原合成酶激酶3 (GSK3)被认为在糖尿病的病理生理中起关键作用
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:
$ 232.34万 - 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:
$ 232.34万 - 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:
$ 232.34万 - 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:
$ 232.34万 - 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:
$ 232.34万 - 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:
$ 232.34万 - 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:
$ 232.34万 - 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:
$ 232.34万 - 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:
$ 232.34万 - 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:
$ 232.34万 - 项目类别:














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