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: 8449414
• 负责人: Andrew G Horti
• 金额: $ 44.24万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449414
• 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; longitudinal course; man; mild neurocognitive 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）： 胆碱能缺乏是阿尔茨海默氏病（AD）患者痴呆严重程度的最强神经化学相关性。对AD患者的几项验尸研究表明，烟碱乙酰胆碱受体（1422-NACHR）的1422-囊型损失在大脑皮层，海马和纹状体，大脑区域，其中度密度为1422-NACHRS，但在丘脑中，但在丘脑中，但在丘脑中，但在丘脑中最高的是1422-NACHS。对合适的正电子发射断层扫描（PET）放射性体的可用性限制了对丘脑外1422-NACHR（ETNR）的体内成像研究。该提案的总体目的是开发一种用于人类受试者ETNR定量宠物成像的放射性物体，这将使研究神经退行性疾病中的烟碱系统，尤其是AD。当前，只有一个放射性物体，即2- [18F] FA，可用于丘脑1422-NACHRS的PET成像，其对ETNR的成像的特性很差。 R21：[18F] Xtra，第一个具有适用于动物ETNRS定量PET成像的特性的放射性物体，最近是由我们的组开发的。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）有效合成[18F] XTRA的辐射标记的前体； （2）小鼠体内药理学和辐射剂量学研究； （3）使用PET在狒狒中进行基线和阻塞实验。在R21阶段结束时，我们将使用[18F] XTRA提交人类研究的探索性IND。 R33：在R33阶段（2-4年）和FDA批准后，[18F] XTRA将被量化用于年轻人类控制受试者大脑中ETNR的药代动力学，分布密度，结合潜力和ETNR的总分布量（18-45岁）。将开发用于定量使用[18F] XTRA在人脑中的ETNR的合适PET模型。在第2年还将获得[18F] XTRA的辐射剂量法，以确保[18F] Xtra对每个受试者进行两次或更多PET扫描的安全性，从而在第2年进行人体测试/重新测试PET扫描。年龄在3年中，年龄在3年中进行了年龄段的人（与年龄的年龄段相比，年龄段）。 4）。与老年人相比，年轻受试者和与年龄匹配的对照组相比，年轻受试者的[18F] XTRA结合在[18F] XTRA结合（额叶和颞皮层，海马和纹状体）中会发生显着差异。我们的长期目标是通过研究AD受体变化和轻度认知障碍的受体变化的纵向方法，评估1422-NACHR作为AD的生物标志物，并测试这些受体的敏感性胆碱能治疗的效果。