Validation of Fluorine-18 radioligand for PET imaging of synaptic density in Alzheimer's disease
验证氟 18 放射性配体对阿尔茨海默病突触密度 PET 成像的效果
基本信息
- 批准号:10078584
- 负责人:
- 金额:$ 76.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease therapyAmericanAmyloid beta-ProteinAutopsyBindingBiological MarkersBlood GlucoseBrainBrain DiseasesCellsClinicClinicalClinical TrialsCommunitiesCoupledDataDementiaDevelopmentDiagnosticDiseaseDisease ProgressionEventFDA approvedFastingFemaleFluorineFrontotemporal DementiaGlycoproteinsGoalsHalf-LifeHippocampus (Brain)HumanImageImpaired cognitionIn VitroIndividualInstitutionInvestigationKeppraKineticsLabelLevetiracetamLimbic SystemMeasuresMedical ImagingMembrane ProteinsMethodsMolecular TargetMonitorMulti-Institutional Clinical TrialMulticenter TrialsNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPathogenesisPathologyPatientsPharmaceutical PreparationsPositron-Emission TomographyPreventiveProductionPropertyProtein IsoformsProteinsProtocols documentationRadioisotopesRegulationReproducibilityResearchResolutionScanningSenile PlaquesSignal TransductionSiteStructureSynapsesSynaptic VesiclesSynaptophysinTestingTracerTreatment EfficacyTreatment ProtocolsTreatment outcomeValidationVesicleabeta oligomeramyloid imaginganalogbasecognitive functiondensityfluorodeoxyglucoseglucose metabolismhuman subjectimaging agentimaging biomarkerimaging propertiesin vivoin vivo imagingkinetic modelmalemild cognitive impairmentnervous system disorderneuroimagingneuroimaging markerneuropsychiatric disorderpre-clinicalpresynapticquantitative imagingradioligandradiotracersynaptic failuretomographytooltraffickinguptakevirtualwhite matter
项目摘要
Alzheimer's disease (AD) is a progressive neurodegenerative disorder afflicting 6 million Americans. The
clinical dementia of AD is coupled to a distinct pathology, with β-amyloid plaques, neurofibrillary tangles, and
synaptic loss. Synapses are essential for cognitive function, and their loss is well established as the major
structural correlate of cognitive impairment in AD. An early event in AD pathogenesis, synaptic failure is
detectable in individuals with the prodromal stage of mild cognitive impairment (MCI).
Positron Emission Tomography (PET) imaging is increasingly employed in the study of AD. However, until
recently there have been no PET radiotracers that can directly image synaptic density in vivo, which would be
of high value in AD diagnosis, as well as in monitoring efficacy of treatments. We have developed 11C-UCB-J
as a radiotracer for PET imaging and quantification of the synaptic vesicle glycoprotein-2A (SV2A). In studies
in healthy human subjects, 11C-UCB-J displayed excellent properties for quantitative PET imaging of SV2A in
the human brain. We have also validated SV2A as an in vivo biomarker for synaptic density. Initial imaging
results in MCI/AD patients show specific and distinct SV2A reductions, most pronounced (30-40%) in the
hippocampus, which is expected and consistent with postmortem studies, where early degeneration of the
entorhinal cortical cell projection to hippocampus and hippocampal SV2A reductions have been observed.
Thus, based on these data, 11C-UCB-J appears to be an excellent radiotracer for quantitative imaging of SV2A
in the human brain and 11C-UCB-J PET can be an extremely useful in vivo biomarker of synaptic loss in AD.
Although 11C-UCB-J proves to be an excellent tracer for synaptic density imaging, a significant drawback is
the short half-life (t1/2 = 20.4 min) of its 11C-radiolabel, which precludes its central production and distribution to
multiple sites for imaging use, and thus limits its wide application in multi-center clinical trials or as diagnostic
agent in clinics. For AD in particular, where drug clinical trials at many institutions are ongoing, the need for a
longer-lived radiotracer is evident and one labeled with the 18F-radioisotope (t1/2 = 109.8 min) will be
appropriate. Analogous to the development of 11C-PIB and its FDA-approved 18F-labeled counterpart 18F-
flutemetamol (Vizamyl®) for β-amyloid imaging in AD, in this application we propose to develop18F-SDM-8, the
difluorinated analog of UCB-J, for human neuroimaging, and to validate its use as a imaging biomarker of
synaptic loss in MCI/AD. The goal is to provide a “neuroimaging biomarker of synaptic density” for use in
the study of the AD continuum and potential diagnosis of AD in its earliest, prodromal stage, as well as in the
monitoring of disease progression and efficacy of emerging AD therapies. In addition to AD, the availability of
18F-SDM-8 PET as a general imaging biomarker of synaptic density will enable the investigation of a wide
range of neuropsychiatric diseases where abnormalities in synaptic density/plasticity are implicated.
阿尔茨海默病(AD)是一种进行性神经退行性疾病,困扰着600万美国人。的
AD的临床痴呆与一种独特的病理学有关,包括β-淀粉样蛋白斑块、神经元缠结和
突触丧失突触对认知功能至关重要,它们的丧失被公认为是
AD认知功能损害结构相关性研究作为AD发病机制中的早期事件,
在轻度认知障碍(MCI)前驱期个体中可检测到。
正电子发射断层扫描(PET)成像越来越多地用于AD的研究。然而直到
最近,还没有PET放射性示踪剂可以直接在体内成像突触密度,这将是不可能的。
在AD诊断以及监测治疗效果方面具有很高的价值。我们开发了11 C-UCB-J
作为突触囊泡糖蛋白-2A(SV 2A)PET成像和定量的放射性示踪剂。研究中
在健康人受试者中,11 C-UCB-J在SV 2A的定量PET成像中显示出优异的性能,
人类的大脑。我们还验证了SV 2A作为突触密度的体内生物标志物。初始成像
MCI/AD患者的结果显示特异性和明显的SV 2A减少,在MCI/AD患者中最明显(30-40%),
海马体,这是预期的,并与死后研究一致,其中早期退化的海马体,
已经观察到内嗅皮质细胞投射到海马和海马SV 2A减少。
因此,基于这些数据,11 C-UCB-J似乎是SV 2A定量成像的良好放射性示踪剂
11 C-UCB-J PET可以是AD中突触丢失的极其有用的体内生物标志物。
尽管11 C-UCB-J被证明是突触密度成像的优良示踪剂,但显著的缺点是
其11 C-放射性标记的半衰期较短(t1/2 = 20.4 min),这妨碍了其集中生产和分布,
用于成像的多个部位,因此限制了其在多中心临床试验或诊断中的广泛应用
诊所的代理人。特别是对于AD,许多机构正在进行药物临床试验,需要
较长寿命的放射性示踪剂是明显的,用18F-放射性同位素标记的一个(t1/2 = 109.8 min)将是
适当类似于11 C-PIB及其FDA批准的18F-标记的对应物18F-的开发,
在本申请中,我们提出开发18F-SDM-8,
UCB-J的二氟化类似物,用于人类神经成像,并验证其作为以下成像生物标志物的用途:
MCI/AD中的突触丢失。其目标是提供一种“突触密度的神经成像生物标志物”,用于
研究AD的连续性和AD在其最早期、前驱期以及
监测疾病进展和新兴AD疗法的疗效。除了AD之外,
18F-SDM-8 PET作为突触密度的一般成像生物标志物将使得能够研究广泛的突触密度。
涉及突触密度/可塑性异常的一系列神经精神疾病。
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)
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YIYUN HENRY HUANG其他文献
YIYUN HENRY HUANG的其他文献
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{{ truncateString('YIYUN HENRY HUANG', 18)}}的其他基金
Sigma-1 Receptor Radioligand for Translational Research in Alzheimer's Disease
用于阿尔茨海默病转化研究的 Sigma-1 受体放射性配体
- 批准号:
10586550 - 财政年份:2023
- 资助金额:
$ 76.44万 - 项目类别:
Sigma-1 Receptor Radioligand for Translational Research in Alzheimer's Disease
用于阿尔茨海默病转化研究的 Sigma-1 受体放射性配体
- 批准号:
10670485 - 财政年份:2022
- 资助金额:
$ 76.44万 - 项目类别:
Validation of Fluorine-18 radioligand for PET imaging of synaptic density in Alzheimer's disease
验证氟 18 放射性配体对阿尔茨海默病突触密度 PET 成像的效果
- 批准号:
10319957 - 财政年份:2020
- 资助金额:
$ 76.44万 - 项目类别:
Validation of Fluorine-18 radioligand for PET imaging of synaptic density in Alzheimer's disease
验证氟 18 放射性配体对阿尔茨海默病突触密度 PET 成像的效果
- 批准号:
10541827 - 财政年份:2020
- 资助金额:
$ 76.44万 - 项目类别:
Novel PET Radiotracer for Muscarinic M1 Receptor
用于毒蕈碱 M1 受体的新型 PET 放射性示踪剂
- 批准号:
9365677 - 财政年份:2017
- 资助金额:
$ 76.44万 - 项目类别:
Novel PET Radiotracer for Muscarinic M1 Receptor
用于毒蕈碱 M1 受体的新型 PET 放射性示踪剂
- 批准号:
10001184 - 财政年份:2017
- 资助金额:
$ 76.44万 - 项目类别:
Novel agonist tracers for PET imaging of kappa opioid receptors
用于 kappa 阿片受体 PET 成像的新型激动剂示踪剂
- 批准号:
8899631 - 财政年份:2011
- 资助金额:
$ 76.44万 - 项目类别:
Novel agonist tracers for PET imaging of kappa opioid receptors
用于 kappa 阿片受体 PET 成像的新型激动剂示踪剂
- 批准号:
8693652 - 财政年份:2011
- 资助金额:
$ 76.44万 - 项目类别:
Novel agonist tracers for PET imaging of kappa opioid receptors
用于 kappa 阿片受体 PET 成像的新型激动剂示踪剂
- 批准号:
8190570 - 财政年份:2011
- 资助金额:
$ 76.44万 - 项目类别:
Novel agonist tracers for PET imaging of kappa opioid receptors
用于 kappa 阿片受体 PET 成像的新型激动剂示踪剂
- 批准号:
8318066 - 财政年份:2011
- 资助金额:
$ 76.44万 - 项目类别:
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