PET imaging of a4b2 nicotinic receptor upregulation and smoking cessation
a4b2 烟碱受体上调和戒烟的 PET 成像
基本信息
- 批准号:9403663
- 负责人:
- 金额:$ 73.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcidsAcuteAddressAffectAffinityBindingBinding SitesBiological AssayBrainBrain DiseasesCategoriesCell LineCell modelCellsCessation of lifeChantixChronicDataDevelopmentExposure toGoalsHumanImageKineticsKnockout MiceLabelLigandsLinkMeasuresMetabolismMethodsModelingMolecular ConformationMusNeuronsNicotineNicotine DependenceNicotinic ReceptorsPharmaceutical PreparationsPositron-Emission TomographyProcessReagentReportingRodentSiteSmokerTestingTobaccoTobacco smokeTobacco smokingTobacco useUnited StatesUp-RegulationVesicleWithdrawaladdictionbasecigarette smokingcravingepibatidineimaging probereceptor upregulationsmoking cessationvarenicline
项目摘要
Abstract
Tobacco continues to be widely used world-wide, primarily via cigarette smoking, and is the leading cause of
preventable deaths in the United States. Tobacco use is driven by nicotine addiction, which starts by nicotine
binding to high-affinity nicotine binding sites in brain. 80-90% of the high-affinity sites are located on 42-type
nicotinic acetylcholine receptors (42Rs). Prolonged nicotine exposure increases high-affinity 42R binding
sites in brain, a process termed “upregulation”, linked to craving and withdrawal in nicotine addiction. This
proposal is based on our recent discovery that 42R ligands that are weak bases, such as the smoking
cessation reagent varenicline (Chantix), can be selectively trapped in 42R-containing acidic vesicles of cells
and neurons. Slow release of trapped varenicline reduces the effects of nicotine upregulation. Selective
trapping is further regulated by nicotine upregulation, which increases the numbers of 42R-containing acidic
vesicles. Nicotine, also a weak base, is not trapped because its ligand pKa and affinity for 42Rs is lower
than that of varenicline. These results provide a new paradigm for how varenicline causes smoking cessation.
They also provide new information about the potential cellular distribution of42R PET probes, all of which
are weak bases. Like varenicline and nicotine, different 42R PET probes have different ligand pKas and
affinities for 42Rs, which explains differences in kinetics, displaceable binding by varenicline and nicotine,
non-displaceable binding and metabolism.
While a number of studies have used PET probes specific for 42R high-affinity binding sites in brain, these
studies are complicated by the interpretations of the binding and binding kinetics especially when nicotine
and/or varenicline are present. Using our concept about the trapping of 42R weak base ligands in
intracellular acidic vesicles, we will develop new cellular and whole models of PET probe kinetics that take into
account 42R ligand trapping in acidic vesicles. There is the potential of wider application of the PET
methods that will be developed in this application, since for 42R PET imaging is currently underway in a
number of brain disorders. The goals of this proposal are to examine how our discovery of the trapping of weak
base 42R ligands in acid vesicles affects the imaging of 42Rs using PET probes and to use PET probe
imaging to examine how nicotine causes 42R upregulation and how varenicline alters upregulation.
摘要
烟草继续在世界范围内被广泛使用,主要是通过吸烟,是导致
在美国,可预防的死亡。烟草的使用是由尼古丁成瘾驱动的,尼古丁是由尼古丁开始的。
结合到大脑中的高亲和力尼古丁结合部位。80%-90%的高亲和力位点位于42型
烟碱型乙酰胆碱受体(42RS)。长期尼古丁暴露增加高亲和力42R结合
大脑中的部位,这一过程被称为“上调”,与尼古丁成瘾的渴望和戒断有关。这
提出的建议是基于我们最近发现的42R配体是弱碱基,如吸烟
止血剂伐伦克林(Chantix)可选择性地被捕获在含有42R的细胞酸性囊泡中
和神经元。缓慢释放捕获的varenicline可减少尼古丁上调的影响。有选择性的
诱捕进一步受到尼古丁上调的调节,这增加了含有42R的酸性物质的数量
水泡。尼古丁也是一种弱碱,由于其配体pKa和对42RS的亲和力较低,因此不会被捕获
比伐伦尼克林强。这些结果为研究varenicline如何导致戒烟提供了一个新的范例。
他们还提供了关于42RPET探针潜在细胞分布的新信息,所有这些
都是薄弱的基础。与Varenicline和尼古丁一样,不同的42RPET探针具有不同的配体pKas和
42RS的亲和力,这解释了动力学上的差异,与varenicline和尼古丁的可置换结合,
不可移位的结合和代谢。
虽然许多研究使用了针对大脑中42R高亲和力结合位点的正电子发射计算机断层扫描探针,但这些
对结合和结合动力学的解释使研究变得复杂,特别是当尼古丁
和/或varenicline存在。利用我们提出的-4--2R弱碱基配体捕获的概念
细胞内的酸性囊泡,我们将开发新的细胞和整个PET探针动力学模型,以
说明42R配体捕获在酸性小泡中。PET有更广泛的应用潜力
将在此应用程序中开发的方法,因为对于42RPET成像目前正在进行中
脑部疾病的数量。这项提议的目标是研究我们如何发现弱者的陷阱
酸性囊泡中碱性-4--2R配体对-4--2RS显影的影响
成像检查尼古丁如何导致42R上调以及varenicline如何改变上调。
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)
专利数量(0)
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Chin-Tu Chen其他文献
Chin-Tu Chen的其他文献
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{{ truncateString('Chin-Tu Chen', 18)}}的其他基金
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通过集成 PET、EPR 和 MR 成像改进缺氧肿瘤区域的放射治疗 - 重新提交 01
- 批准号:
9897365 - 财政年份:2020
- 资助金额:
$ 73.29万 - 项目类别:
Improved Radiation Therapy of Hypoxic Tumor Regions by Integrated PET, EPR, and MR Imaging - Resubmission 01
通过集成 PET、EPR 和 MR 成像改进缺氧肿瘤区域的放射治疗 - 重新提交 01
- 批准号:
10544779 - 财政年份:2020
- 资助金额:
$ 73.29万 - 项目类别:
Improved Radiation Therapy of Hypoxic Tumor Regions by Integrated PET, EPR, and MR Imaging - Resubmission 01
通过集成 PET、EPR 和 MR 成像改进缺氧肿瘤区域的放射治疗 - 重新提交 01
- 批准号:
10314063 - 财政年份:2020
- 资助金额:
$ 73.29万 - 项目类别:
Improved Radiation Therapy of Hypoxic Tumor Regions by Integrated PET, EPR, and MR Imaging - Resubmission 01 - Revision - 1
通过集成 PET、EPR 和 MR 成像改进缺氧肿瘤区域的放射治疗 - 重新提交 01 - 修订版 - 1
- 批准号:
10289582 - 财政年份:2020
- 资助金额:
$ 73.29万 - 项目类别:
PET imaging of a4b2 nicotinic receptor upregulation and smoking cessation
a4b2 烟碱受体上调和戒烟的 PET 成像
- 批准号:
9919536 - 财政年份:2017
- 资助金额:
$ 73.29万 - 项目类别:
PET imaging of a4b2 nicotinic receptor upregulation and smoking cessation
a4b2 烟碱受体上调和戒烟的 PET 成像
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10152562 - 财政年份:2017
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An MR-Compatible Small Animal SPECT Based on Artifical Compound Eye Cameras
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