Subtype-selective phosphodiesterase PET ligands
亚型选择性磷酸二酯酶 PET 配体
基本信息
- 批准号:10568308
- 负责人:
- 金额:$ 78.25万
- 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:2023-01-01 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:ABCB1 geneAffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAmyloid beta-ProteinAutopsyAutoradiographyBehaviorBindingBinding ProteinsBiochemical ProcessBiodistributionBiologicalBiological AssayBiological ProcessBlood specimenBrainCentral Nervous System DiseasesCerebellumCharacteristicsChemistryCorpus striatum structureCyclic AMPDevelopmentDockingDoseEnzymesEvaluationExhibitsFamilyFunctional disorderGenerationsGoalsHumanImageImaging DeviceImaging ligandsImmune responseIn VitroInflammatory ResponseKineticsKnockout MiceKnowledgeLabelLeadLibrariesLigandsLiver MicrosomesMediatingMemoryMetabolic Clearance RateMethylationMolecularMonitorNational Institute of Mental HealthNeurodegenerative DisordersNeuroimmunePermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPlasmaPlasma ProteinsPlayPontine structurePositioning AttributePositronPositron-Emission TomographyProcessRadiolabeledResearchRodentRoleScientific Advances and AccomplishmentsSelection CriteriaSignal TransductionSiteSpecificityTestingToxic effectTransgenic OrganismsTranslationsUnited StatesValidationVisualizationWestern BlottingWorkabeta depositionbrain tissueclinical translationdesigndrug discoveryimage translationimaging studyimmunoregulationimprovedin vivoin vivo evaluationinhibitorkinetic modellipophilicitymolecular imagingmouse modelnervous system disordernonhuman primatenovelphosphoric diester hydrolaseradioligandresponsetau-1transgenic model of alzheimer diseaseuptake
项目摘要
Project Summary. As a major cAMP-specific hydrolyzing enzyme, PDE7 plays a significant role in modulating
immune and inflammatory response in a variety of neurodegenerative diseases, including Alzheimer’s disease (AD).
PDE7 treatment not only improved the memory and behavior in transgenic models of AD but also exhibited decreased
brain Aβ deposition, enhanced Aβ degradation, and decreased tau phosphorylation. The mechanism of action was
mediated via the cAMP-specific neuroinmmune response in AD. Positron emission tomograohy (PET) is capable of
quantifying biochemical processes in vivo, and a suitable PDE7 ligand would substantially improve our understanding
of such cAMP-mediated signaling under different pathophysiological AD conditions, otherwise inaccessible by ex vivo
(destructive) analysis. Quantification of PDE7 in living brain by PET would also provide the assessment of distribution,
target engagement and dose occupancy of new PDE7-targeted neurotherapeutics. To date, no successful examples
have been demonstrated to image PDE7 in human, representing a significant deficiency of our ability to study this
target in vivo. Therefore, we propose to develop a novel PDE7 PET ligand that can fill this void as the first successful
and translational imaging tool.
We are the first groups to develop PDE7-specific ligands in cross-species PET studies, including [11C]P7-2104
developed in 2021. However, this ligand was discontinued due to marginal binding specificity in vivo. In our 2nd
generation, we identified a lead molecule, P7-2526, which showed high binding affinity and excellent selectivity. Our
preliminary evaluation confirmed that we have overcome the two major obstacles for PDE7 ligand development by
achieving: 1) substantially-improved binding affinity, representing the best compound to date; and 2) high target
specificity (characteristic high uptake in PDE7-rich striatum and low in PDE7-poor cerebellum/pons, which was
validated by LC-MS and Western blotting). Though P7-2526 is a promising lead for new PDE7-targeted ligands, further
optimization for improved binding specificity with proper brain kinetics are sought for translational cross-species
(rodents and nonhuman primates) imaging studies to achieve optimal PDE7 quantification for drug discovery and
clinical translation for AD patients.
On the basis that P7-2526 serves a validated lead for medicinal chemistry optimization, as specific goals, we will
design and prepare a focused library of PDE7-specific modulators amenable for labeling with 11C or 18F, and evaluate
their ability to quantify PDE7 activity 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 high-affinity and selective PDE7 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。PDE7作为一种主要的camp特异性水解酶,在camp的调控中起着重要的作用
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 78.25万 - 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:
$ 78.25万 - 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:
$ 78.25万 - 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:
$ 78.25万 - 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:
$ 78.25万 - 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:
$ 78.25万 - 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:
$ 78.25万 - 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:
$ 78.25万 - 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:
$ 78.25万 - 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:
$ 78.25万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Continuing Grant