Extrathalamic nAChR-PET for Imaging Neurodegeneration
丘脑外 nAChR-PET 用于神经退行性疾病成像
基本信息
- 批准号:8713891
- 负责人:
- 金额:$ 40.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-03-01 至 2016-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityAgeAlzheimer&aposs DiseaseAmyloidAmyloid depositionAnimalsAutopsyBasal GangliaBehavioral SymptomsBindingBiological MarkersBolus InfusionBrainBrain regionCerebral cortexCerebrumCholinergic ReceptorsCorpus striatum structureDataDementiaDevelopmentDiseaseDopamineDrug AddictionDrug KineticsElderlyExhibitsFunctional disorderGlutamatesGoalsHealthHippocampus (Brain)HumanImageImpaired cognitionKineticsLigandsMental disordersMethodsModelingMusNerve DegenerationNeurobehavioral ManifestationsNeurodegenerative DisordersNeurotransmittersNicotine DependenceNicotinic ReceptorsOutcomePapioParkinson DiseasePatientsPharmaceutical PreparationsPharmacologyPhasePhysiciansPositron-Emission TomographyPrevalencePropertyRadioactiveRadiolabeledRadiometryRelative (related person)RoleSafetySamplingSchizophreniaSerotoninSeveritiesSignal PathwaySiteSystemTemporal LobeTestingThalamic structureToxic effectWhole-Body Irradiationamyloid peptidebasecholinergiccytisinedensityfrontal lobehuman subjectin vivoin vivo imaginglongitudinal coursemanmild cognitive impairmentneurochemistrynonhuman primatenormal agingpreclinical studyputamenradioligandradiotracerreceptorreceptor sensitivityresearch studysingle photon emission computed tomographytherapeutic target
项目摘要
DESCRIPTION (provided by applicant):
The cholinergic deficit is the strongest neurochemical correlate of the severity of dementia in patients with Alzheimer's disease (AD). Several post-mortem studies of patients with AD have demonstrated the loss of the 1422-subtype of the nicotinic acetylcholine receptor (1422-nAChR) in the cerebral cortex, hippocampus and striatum, brain regions with a moderate density of 1422-nAChRs, but not in thalamus, a region with the highest density of 1422-nAChRs. In vivo imaging studies of extrathalamic 1422-nAChRs (ETNRs) have been limited by the availability of suitable positron emission tomography (PET) radioligands. The overall objective of this proposal is to develop a radioligand for quantitative PET imaging of ETNR in human subjects that will make it possible to investigate the nicotinic system in neurodegenerative disorders, especially AD. Currently, only one radioligand, 2-[18F]FA, is available for PET imaging of thalamic 1422-nAChRs and its properties for imaging of ETNRs are poor. R21: [18F]XTRA, the first radioligand with properties suitable for quantitative PET imaging of the ETNRs in animals, was recently developed by our group. In the R21 phase (Year 1) we will perform pre-clinical studies with [18F]XTRA that include (1) efficient synthesis of precursor for radiolabeling of [18F]XTRA; (2) in vivo pharmacology and radiation dosimetry studies in mice; and (3) baseline and blocking experiments in baboons using PET. By the end of the R21 phase we will file an exploratory IND for human studies with [18F]XTRA. R33: In the R33 phase (Years 2-4) and after FDA approval of the eIND, [18F]XTRA, will be quantified for pharmacokinetics, distribution density, binding potential and total distribution volume of the ETNRs in the brain of young human control subjects (18-45 years old). Appropriate PET models for quantification of ETNRs with [18F]XTRA in human brain will be developed. Radiation dosimetry of [18F]XTRA in humans will be also obtained in Year 2 to assure the safety of [18F]XTRA for two or more PET scans per subject, enabling human test/re-test PET scans in Year 2. PET experiments in elderly human control subjects (over age 60) will be performed in Year 3. The results of those experiments will be compared with PET scans of age-matched patients with AD (over age 60) (Year 4). Significant differences are expected in [18F]XTRA binding in the extrathalamic regions (frontal and temporal cortices, hippocampus and striatum) in young subjects compared to elderly people and in patients with AD compared to age-matched controls. Our long term goals are to evaluate 1422-nAChR as a biomarker of AD by studying the longitudinal course of receptor changes in AD and mild cognitive impairment and to test the sensitivity of these receptors the effects of cholinergic treatment.
描述(由申请人提供):
胆碱能缺陷是阿尔茨海默病(AD)患者痴呆严重程度的最强神经化学相关性。对AD患者的几项尸检研究表明,大脑皮质、海马和纹状体(具有中等密度1422-nAChR的大脑区域)中的1422-亚型尼古丁乙酰胆碱受体(1422-nAChR)丢失,但不在丘脑中,这是1422-nAChR密度最高的区域。丘脑外1422-nAChRs(ETNRs)的体内成像研究受到合适的正电子发射断层扫描(PET)放射性配体的限制。该提案的总体目标是开发用于人类受试者ETNR定量PET成像的放射性配体,这将使研究神经退行性疾病,特别是AD中的烟碱系统成为可能。目前,只有一种放射性配体2-[18 F]FA可用于丘脑1422-nAChR的PET成像,并且其用于ETNR成像的性质较差。R21:[18F]XTRA是我们小组最近开发的第一种具有适用于动物ETNR定量PET成像特性的放射性配体。在R21阶段(第1年),我们将进行[18 F]XTRA临床前研究,包括(1)有效合成[18 F]XTRA放射性标记前体;(2)小鼠体内药理学和辐射剂量测定研究;(3)使用PET在狒狒中进行基线和阻断实验。在R21阶段结束时,我们将提交[18 F]XTRA人体研究的探索性IND。R33:在R33阶段(第2-4年)和FDA批准eIND后,将定量测定年轻人对照受试者(18-45岁)脑中ETNR的药代动力学、分布密度、结合潜力和总分布体积。将开发用于在人脑中用[18 F]XTRA定量ETNR的适当PET模型。还将在第2年获得人体[18 F]XTRA的辐射剂量测定,以确保每例受试者进行两次或更多次PET扫描时[18 F]XTRA的安全性,从而能够在第2年进行人体试验/复检PET扫描。将在第3年对老年人对照受试者(60岁以上)进行PET实验。这些实验的结果将与年龄匹配的AD患者(60岁以上)(第4年)的PET扫描进行比较。预期年轻受试者与老年人相比以及AD患者与年龄匹配的对照组相比,丘脑外区域(额叶和颞叶皮质、海马和纹状体)的[18 F]XTRA结合存在显著差异。我们的长期目标是通过研究AD和轻度认知障碍中受体变化的纵向过程来评估1422-nAChR作为AD的生物标志物,并测试这些受体对胆碱能治疗效果的敏感性。
项目成果
期刊论文数量(1)
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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Andrew G Horti其他文献
Andrew G Horti的其他文献
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