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: 9403663
• 负责人: Chin-Tu Chen
• 金额: $ 73.29万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9403663
• 关键词: Acids; Acute; Address; Affect; Affinity; Binding; Binding Sites; Biological Assay; Brain; Brain Diseases; Categories; Cell Line; Cell model; Cells; Cessation of life; Chantix; Chronic; Data; Development; Exposure to; Goals; Human; Image; Kinetics; Knockout Mice; Label; Ligands; Link; Measures; Metabolism; Methods; Modeling; Molecular Conformation; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Reagent; Reporting; Rodent; Site; Smoker; Testing; Tobacco; Tobacco smoke; Tobacco smoking; Tobacco use; United States; Up-Regulation; Vesicle; Withdrawal; addiction; base; cigarette smoking; craving; epibatidine; imaging probe; receptor upregulation; smoking cessation; varenicline

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 42-type nicotinic acetylcholine receptors (42Rs). Prolonged nicotine exposure increases high-affinity 42R 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 42R ligands that are weak bases, such as the smoking cessation reagent varenicline (Chantix), can be selectively trapped in 42R-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 42R-containing acidic vesicles. Nicotine, also a weak base, is not trapped because its ligand pKa and affinity for 42Rs 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 of42R PET probes, all of which are weak bases. Like varenicline and nicotine, different 42R PET probes have different ligand pKas and affinities for 42Rs, 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 42R 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 42R weak base ligands in intracellular acidic vesicles, we will develop new cellular and whole models of PET probe kinetics that take into account 42R 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 42R 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 42R ligands in acid vesicles affects the imaging of 42Rs using PET probes and to use PET probe imaging to examine how nicotine causes 42R upregulation and how varenicline alters upregulation.

抽象的 烟草继续在全球范围内广泛使用，主要是通过吸烟，是 美国可预防的死亡。烟草的使用是由尼古丁成瘾驱动的，尼古丁开始 与大脑中的高亲和力尼古丁结合位点结合。 80-90％的高亲和力站点位于42型上 尼古丁乙酰胆碱受体（42R）。长时间的尼古丁暴露会增加高亲和力42R结合 大脑中的站点是一个称为“上调”的过程，与尼古丁成瘾中的渴望和戒断有关。这 提案是基于我们最近发现的，42R配体是弱碱的，例如吸烟 停止试剂varenicline（chantix）可以选择性地捕获在含42R的细胞的酸性蔬菜中 和神经元。缓慢释放被捕获的varenicline减少了尼古丁上调的影响。选择性 尼古丁上调进一步调节诱捕 因素。尼古丁（也是一个弱的基础）并没有被困，因为它的配体PKA和对42RS的亲和力较低 比varenicline。这些结果为葡萄泳如何引起戒烟提供了新的范式。 他们还提供了有关潜在的细胞分布的新信息42RPET问题，所有这些 是薄弱的基础。像Varenicline和Nicotine一样，不同的42RPET探针具有不同的配体PKA，并且 42RS的亲和力解释了动力学的差异，可取代的varenicline和nicotine的差异， 不可移植的结合和代谢。 虽然许多研究使用了针对大脑中42R高亲和力结合位点的宠物问题，但 研究和结合动力学的解释使研究变得复杂，尤其是当尼古丁时 存在和/或varinicline。利用我们关于捕获42R弱碱配体的概念 细胞内酸性蔬菜，我们将开发出新的细胞和整个PET探针动力学模型 考虑酸性蔬菜中的42R配体捕获。宠物有可能更广泛地应用 该应用程序将在此应用中开发的方法，因为目前正在进行42RPET成像 脑部疾病的数量。该提案的目标是研究我们如何发现薄弱的陷阱 酸性蔬菜中的碱基42R配体使用PET探针影响42R的成像，并使用PET探针 成像以检查尼古丁如何引起42R上调以及Varenicline如何改变上调。