In Vitro and In Vivo Characterization of Alpha-Synuclein PET Radiotracers
α-突触核蛋白 PET 放射性示踪剂的体外和体内表征
基本信息
- 批准号:10023219
- 负责人:
- 金额:$ 106.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-24 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffinityAlzheimer&aposs DiseaseAmyloid beta-ProteinAtaxiaAutonomic DysfunctionAutopsyAutoradiographyBindingBinding SitesBiodistributionBiological AssayBrainCellsClinicalClinical ResearchCommunicationCryoelectron MicroscopyCytoplasmic InclusionDataDepositionDevelopmentDiseaseDisease ProgressionGenesGoalsHumanImageImaging ligandsIn VitroIndividualKineticsLabelLaboratoriesLeadLevodopaLewy BodiesLewy Body DementiaLewy neuritesLigandsMacacaMeasuresMovement DisordersMultiple System AtrophyMutationNational Institute of Neurological Disorders and StrokeNeocortexNerve DegenerationNeuronsParkinson DiseaseParkinson&aposs DementiaParkinsonian DisordersPathogenesisPathologicPharmaceutical ChemistryPositron-Emission TomographyProcessPropertyProteinsRadiochemistryRattusRecombinantsResearchRodentRoleSamplingSeriesStructureStructure-Activity RelationshipTeleconferencesTherapeuticTimeTissuesTracerValidationabeta accumulationalpha synucleinbasecerebral atrophydensitydiagnostic accuracyhuman tissueimaging agentimaging studyimprovedin silicoin vivomeetingsmembermicroPETmouse modelnonhuman primatepreventprogramsprogression markerprotein TDP-43protein structureradioligandradiotracerscreeningsynucleinopathytargeted biomarkertau Proteinstau aggregationtissue preparationuptake
项目摘要
PROJECT 1: Development of Alpha Synuclein PET Radioligands for Imaging Synucleinopathies
The goal of Project 1 is to conduct a series of in vitro binding studies, in vivo brain uptake and PET imaging
studies in the process of evaluating radiotracers for imaging aggregated alpha synuclein (Asyn) in the
synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple
system atrophy (MSA). The compounds evaluated in this project will be identified via in silico ultrahigh
throughput screening and traditional structure-activity relationship (SAR) studies conducted in the Medicinal
Chemistry and Radiochemistry (MCRC) Core. The in vitro binding assays described in this project will consist
of three different types: 1) screening of “in silico hits” in Asyn fibrils using radioligands for the different binding
sites with the goal of identifying “fibril confirmed hits”; 2) in vitro binding assays of the fibril confirmed hits to
identify new lead compounds having an affinity for ASyn in PD and MSA tissue of <50 nM; and, 3) indirect and
direct binding assays of compounds developed as part of the SAR studies in the MCRC Core targeting or more
of the binding sites in Asyn fibrils. Compounds having a high affinity for Asyn and good selectivity versus other
proteinopathies (Abeta, tau and TDP43) will be advanced to a series of in vitro autoradiography and in vivo
studies as a means of identifying a suitable candidate(s) for translational imaging studies in humans. Another
function of Project 1 is to cross-validate potential PET radiotracers having a high affinity for 4R tau developed by
the MCRC Core and evaluated in Project 2. The successful accomplishment of the research objectives of this
U19 Center will require the frequent communication between the members of the MCRC Core, Project 1 and
Project 2. This will be accomplished by through the series of bi-weekly teleconference calls and meetings of the
Center Steering Committee, External Liaison Committee, and NINDS program staff as outlined in the
administrative Core. The ultimate goal of the research described in Project 1 is to identify radiotracers for the
different synucleinopathies that will be conducted in translational imaging studies described in the Clinical Core.
项目1:用于突触核蛋白病成像的α突触核蛋白PET放射性配体的开发
项目1的目标是进行一系列体外结合研究、体内脑摄取和PET成像
在评估放射性示踪剂用于成像聚集的α突触核蛋白(Asyn)的过程中的研究
突触核蛋白病,其包括帕金森病(PD)、路易体痴呆(DLB)和多发性硬化症。
系统萎缩(MSA)。本项目中评价的化合物将通过计算机模拟鉴定
在Medicinal中进行的通量筛选和传统的结构-活性关系(SAR)研究
化学与放射化学(MCRC)本项目中描述的体外结合试验将包括
1)使用放射性配体筛选Asyn原纤维中的“计算机命中”,用于不同的结合
目的是鉴定“原纤维确认的命中”的位点; 2)原纤维确认的命中与
鉴定对PD和MSA组织中ASyn具有<50 nM亲和力的新先导化合物;和,3)间接和
作为MCRC核心靶向或更高SAR研究的一部分开发的化合物的直接结合试验
的结合位点。具有对Asyn的高亲和力和相对于其它化合物的良好选择性的化合物
蛋白质病(Abeta、tau和TDP 43)将被推进到一系列体外放射自显影和体内放射自显影。
研究作为一种手段,确定一个合适的候选人(S)在人类翻译成像研究。另一
项目1的功能是交叉验证对4 R tau具有高亲和力的潜在PET放射性示踪剂,
MCRC核心,并在项目2中进行评估。本课题研究目标的顺利完成,
U19中心将要求MCRC核心成员、项目1和
项目2.这将通过一系列双周电话会议和
中心指导委员会、外部联络委员会和NINDS项目工作人员,
行政核心。项目1中描述的研究的最终目标是确定放射性示踪剂,
将在临床核心中描述的翻译成像研究中进行的不同突触核蛋白病。
项目成果
期刊论文数量(0)
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专利数量(0)
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In Vitro and In Vivo Characterization of Alpha-Synuclein PET Radiotracers
α-突触核蛋白 PET 放射性示踪剂的体外和体内表征
- 批准号:
10241512 - 财政年份:2019
- 资助金额:
$ 106.94万 - 项目类别:
Center without Walls for Imaging Proteinopathies with PET (CW2IP2)
PET 蛋白病成像无壁中心 (CW2IP2)
- 批准号:
10613207 - 财政年份:2019
- 资助金额:
$ 106.94万 - 项目类别:
Center without Walls for Imaging Proteinopathies with PET (CW2IP2)
PET 蛋白病成像无壁中心 (CW2IP2)
- 批准号:
10649656 - 财政年份:2019
- 资助金额:
$ 106.94万 - 项目类别: