Extrathalamic nAChR-PET for Imaging Neurodegeneration

丘脑外 nAChR-PET 用于神经退行性疾病成像

• 批准号: 8713891
• 负责人: Andrew G Horti
• 金额: $ 40.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8713891
• 关键词: Address; Affect; Affinity; Age; Alzheimer' s Disease; Amyloid; Amyloid deposition; Animals; Autopsy; Basal Ganglia; Behavioral Symptoms; Binding; Biological Markers; Bolus Infusion; Brain; Brain region; Cerebral cortex; Cerebrum; Cholinergic Receptors; Corpus striatum structure; Data; Dementia; Development; Disease; Dopamine; Drug Addiction; Drug Kinetics; Elderly; Exhibits; Functional disorder; Glutamates; Goals; Health; Hippocampus (Brain); Human; Image; Impaired cognition; Kinetics; Ligands; Mental disorders; Methods; Modeling; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurotransmitters; Nicotine Dependence; Nicotinic Receptors; Outcome; Papio; Parkinson Disease; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physicians; Positron-Emission Tomography; Prevalence; Property; Radioactive; Radiolabeled; Radiometry; Relative (related person); Role; Safety; Sampling; Schizophrenia; Serotonin; Severities; Signal Pathway; Site; System; Temporal Lobe; Testing; Thalamic structure; Toxic effect; Whole-Body Irradiation; amyloid peptide; base; cholinergic; cytisine; density; frontal lobe; human subject; in vivo; in vivo imaging; longitudinal course; man; mild cognitive impairment; neurochemistry; nonhuman primate; normal aging; preclinical study; putamen; radioligand; radiotracer; receptor; receptor sensitivity; research study; single photon emission computed tomography; therapeutic target

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。一些对AD患者的尸检研究表明，在大脑皮层、海马体和纹状体中，1422-nAChR亚型烟碱型乙酰胆碱受体(1422-nAChR)丢失，大脑中密度中等的1422-nAChRs区域，但在丘脑，一个密度最高的区域1422-nAChR没有丢失。丘脑外区1422-nAChRs(ETNRs)的体内成像研究一直受到合适的正电子发射断层扫描(PET)放射配基的可用性的限制。这项建议的总体目标是开发一种用于对人体ETNR进行定量PET成像的放射性配基，这将使研究神经退行性疾病，特别是AD的尼古丁系统成为可能。目前，只有一种放射性配基2-[18F]FA可用于丘脑1422-nAChRs的PET成像，且其对ETNRs的成像性能较差。R21：[18F]Xtra是本课题组最近开发的第一个适用于动物ETNRs定量PET成像的放射性配体。在R21阶段(第1年)，我们将使用[18F]Xtra进行临床前研究，其中包括：(1)高效合成用于放射性标记的[18F]Xtra前体；(2)在小鼠身上进行体内药理学和辐射剂量学研究；以及(3)使用正电子发射计算机断层扫描(PET)在狒狒身上进行基线和阻断实验。到R21阶段结束时，我们将向[18F]Xtra提交一份用于人体研究的探索性IND。R33：在R33阶段(第2-4年)和FDA批准EIND后，[18F]Xtra将量化ETNRs在年轻对照组受试者(18-45岁)大脑中的药代动力学、分布密度、结合潜力和总分布体积。将开发合适的PET模型，用于定量测定人脑中含有[18F]Xtra的ETNRs。人体内[18F]Xtra的辐射剂量测定也将在第二年获得，以确保每个受试者进行两次或更多PET扫描的[18F]Xtra的安全性，从而在第二年进行人体测试/重新测试PET扫描。在老年人类对照组受试者(60岁以上)中进行的PET实验将在第三年进行。这些实验的结果将与年龄匹配的AD患者(60岁以上)(4岁)的PET扫描进行比较。青年受试者与老年人和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、海马体和纹状体)的[18F]Xtra结合预计会有显著差异。我们的长期目标是通过研究1422-nAChR在AD和轻度认知损害中受体变化的纵向过程来评估1422-nAChR作为AD生物标志物的作用，并测试这些受体的敏感性和胆碱能治疗的效果。