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
• 负责人: Chin-Tu Chen
• 金额: $ 69.14万
• 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/9919536
• 关键词: Acids; Acute; Address; Affect; Affinity; Binding; Binding Sites; Biological Assay; Brain; Brain Diseases; Categories; Cell Line; Cell model; Cells; Chantix; Chronic; Data; Development; 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 behavior; Tobacco use; United States; Up-Regulation; Vesicle; Withdrawal; addiction; base; cigarette smoking; craving; epibatidine; imaging probe; nicotine exposure; preventable death; 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 α4β2-type nicotinic acetylcholine receptors (α4β2Rs). Prolonged nicotine exposure increases high-affinity α4β22R 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 α4β2R ligands that are weak bases, such as the smoking cessation reagent varenicline (Chantix), can be selectively trapped in α4β2R-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 α4β2R-containing acidic vesicles. Nicotine, also a weak base, is not trapped because its ligand pKa and affinity for α4β22Rs 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 α4β22R PET probes, all of which are weak bases. Like varenicline and nicotine, different α4β2R PET probes have different ligand pKas and affinities for α4β2Rs, 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 α4β22R 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 α4β2R weak base ligands in intracellular acidic vesicles, we will develop new cellular and whole models of PET probe kinetics that take into account α4β2R 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 α4β2R 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 α4β2R ligands in acid vesicles affects the imaging of α4β2Rs using PET probes and to use PET probe imaging to examine how nicotine causes α4β2R 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％的高亲和力位点位于α4β2型上 尼古丁乙酰胆碱受体（α4β2R）。长时间的尼古丁暴露增加了高亲和力α4β22R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，即弱碱基的α4β2R配体，例如吸烟 停止试剂varenicline（Chantix）可以选择性地捕获在含α4β2R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，这增加了含α4β2R的酸性的数量 工厂。尼古丁（也是一个弱基碱）并没有被困，因为其配体PKA和对α4β22RS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α4β22RPET问题潜在细胞分布的新信息， 是薄弱的基础。像差异线和尼古丁一样，不同的α4β2RPET探针具有不同的配体PKA，并且 α4β2RS的亲和力解释了动力学的差异，可取代的varenicline和尼古丁的结合， 不可移植的结合和代谢。 虽然许多研究使用了针对大脑中α4β22R高亲和力结合位点的PET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α4β2R弱碱配体中的概念 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α4β2R配体捕获。宠物有可能更广泛地应用 在此应用中将开发的方法，因为对于α4β2RPET成像目前正在A中 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 酸蔬菜中的碱基α4β2R配体使用PET探针影响α4β2R的成像，并使用PET探针 成像以检查尼古丁如何引起α4β2R上调以及Varenicline如何改变上调。