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: 8047647
• 负责人: Andrew G Horti
• 金额: $ 23.52万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047647
• 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. PUBLIC HEALTH RELEVANCE: Development of radioligands for positron emission tomography (PET) imaging of the extrathalamic nicotinic receptors (ET 1422-nAChR) is of great importance for studying the role of the nicotinic system in neurodegenerative disorders, schizophrenia, drug dependence and a variety of other disorders as well as for developing nicotinic medications to treat these conditions.

描述（由申请人提供）： 胆碱能缺陷是与阿尔茨海默病（AD）患者痴呆严重程度最强的神经化学相关性。几项针对 AD 患者的尸检研究表明，大脑皮层、海马和纹状体（1422-nAChR 密度适中的大脑区域）中烟碱乙酰胆碱受体 (1422-nAChR) 的 1422 亚型缺失，但并非如此。丘脑中 1422-nAChR 密度最高的区域。丘脑外 1422-nAChR (ETNR) 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一种用于人类受试者 ETNR 定量 PET 成像的放射性配体，这将使研究神经退行性疾病（尤其是 AD）中的烟碱系统成为可能。目前，只有一种放射性配体2-[18F]FA可用于丘脑1422-nAChRs的PET成像，并且其对ETNRs成像的性能较差。 R21：[18F]XTRA是我们小组最近开发的第一个具有适合动物ETNR定量PET成像特性的放射性配体。在R21阶段（第一年），我们将使用[18F]XTRA进行临床前研究，包括（1）有效合成用于放射性标记[18F]XTRA的前体； (2)小鼠体内药理学和放射剂量测定研究； (3) 使用 PET 对狒狒进行基线和阻断实验。在 R21 阶段结束时，我们将使用 [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）以及 FDA 批准 eIND 后，将量化 [18F]XTRA 的药代动力学、分布密度、结合潜力和年轻人类对照大脑中 ETNR 的总分布体积受试者（18-45岁）。将开发适当的 PET 模型，用于用 [18F]XTRA 量化人脑中的 ETNR。还将在第 2 年获得人体 [18F]XTRA 的辐射剂量测定，以确保每个受试者进行两次或多次 PET 扫描时 [18F]XTRA 的安全性，从而能够在第 2 年进行人体测试/重新测试 PET 扫描。老年人类对照受试者（60 岁以上）将在第 3 年进行。这些实验的结果将与年龄匹配的 AD 患者（60 岁以上）的 PET 扫描进行比较（年4）。预计年轻受试者与老年人以及 AD 患者与年龄匹配对照者相比，丘脑外区域（额叶和颞叶皮质、海马和纹状体）的 [18F]XTRA 结合存在显着差异。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 生物标志物，并测试这些受体对胆碱能治疗效果的敏感性。 公共健康相关性：开发用于丘脑外烟碱受体（ET 1422-nAChR）正电子发射断层扫描（PET）成像的放射性配体对于研究烟碱系统在神经退行性疾病、精神分裂症、药物依赖和各种疾病中的作用具有重要意义。其他疾病以及开发烟碱类药物来治疗这些疾病。

项目成果

Recent PET radioligands with optimal brain kinetics for imaging nicotinic acetylcholine receptors.

最近的 PET 放射性配体具有最佳的脑动力学，可用于烟碱乙酰胆碱受体成像。

• 发表时间: 2013-03
• 影响因子: 1.8
• 作者: Horti, Andrew G;Kuwabara, Hiroto;Holt, Daniel P;Dannals, Robert F;Wong, Dean F
• 通讯作者: Wong, Dean F

Synthesis and Preliminary Biological Evaluation of Indol-3-yl-oxoacetamides as Potent Cannabinoid Receptor Type 2 Ligands.

作为有效大麻素受体 2 型配体的 Indol-3-yl-oxoacetamides 的合成和初步生物学评价。

• 发表时间: 2017-01-04
• 作者: Moldovan, Rareş;Deuther;Horti, Andrew G;Brust, Peter
• 通讯作者: Brust, Peter

[(125)I]Iodo-ASEM, a specific in vivo radioligand for α7-nAChR.

[(125)I]Iodo-ASEM，α7-nAChR 的特异性体内放射性配体。

• DOI: 10.1016/j.nucmedbio.2014.12.008
• 发表时间: 2015-05
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Gao Y;Mease RC;Olson TT;Kellar KJ;Dannals RF;Pomper MG;Horti AG
• 通讯作者: Horti AG

Imaging α4β2 Nicotinic Acetylcholine Receptors (nAChRs) in Baboons with [18F]XTRA, a Radioligand with Improved Specific Binding in Extra-Thalamic Regions.

使用 [18F]XTRA 对狒狒中的α4β2 烟碱乙酰胆碱受体 (nAChR) 进行成像，[18F]XTRA 是一种在丘脑外区域具有改进的特异性结合的放射性配体。

• 发表时间: 2017
• 影响因子: 3.1
• 作者: Kuwabara, Hiroto;Gao, Yongjun;Stabin, Michael;Coughlin, Jennifer;Nimmagadda, Sridhar;Dannals, Robert F;Pomper, Martin G;Horti, Andrew G
• 通讯作者: Horti, Andrew G

Development of [(18)F]ASEM, a specific radiotracer for quantification of the α7-nAChR with positron-emission tomography.

开发[(18)F]ASEM，一种用于用正电子发射断层扫描定量α7-nAChR 的特定放射性示踪剂。

• DOI: 10.1016/j.bcp.2015.07.030
• 发表时间: 2015-10-15
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Horti AG