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: 10152562
• 负责人: Chin-Tu Chen
• 金额: $ 68.1万
• 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/10152562
• 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 烟草继续在世界范围内广泛使用，主要是通过吸烟，并且是导致健康问题的主要原因 美国可预防的死亡。烟草使用是由尼古丁成瘾驱动的，而尼古丁成瘾始于尼古丁 与大脑中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 烟碱乙酰胆碱受体（α4β2Rs）。长时间接触尼古丁会增加高亲和力 α4β22R 结合 大脑中的位点，这一过程被称为“上调”，与尼古丁成瘾的渴望和戒断有关。这 该提议基于我们最近发现α4β2R配体是弱碱基，例如吸烟 戒烟试剂伐尼克兰（Chantix），可以选择性地捕获在含有α4β2R的细胞酸性囊泡中 和神经元。缓慢释放的伐尼克兰可降低尼古丁上调的影响。选择性 尼古丁上调进一步调节捕获，从而增加含有 α4β2R 的酸性物质的数量 囊泡。尼古丁也是一种弱碱，不会被捕获，因为它的配体 pKa 和对 α4β22Rs 的亲和力较低 比伐尼克兰。这些结果为伐尼克兰如何导致戒烟提供了新的范例。 他们还提供了有关 α4β22R PET 探针潜在细胞分布的新信息，所有这些 都是弱碱基。与伐尼克兰和尼古丁一样，不同的 α4β2R PET 探针具有不同的配体 pKa 和 α4β2R 的亲和力，这解释了动力学差异、伐尼克兰和尼古丁的可置换结合， 不可置换的结合和代谢。 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 探针，但这些研究 研究因结合和结合动力学的解释而变得复杂，尤其是当尼古丁 和/或伐尼克兰存在。使用我们关于捕获 α4β2R 弱碱配体的概念 细胞内酸性囊泡，我们将开发新的 PET 探针动力学细胞模型和整体模型，该模型考虑了 说明α4β2R配体被捕获在酸性囊泡中。 PET具有更广泛应用的潜力 将在本应用中开发的方法，因为目前正在进行 α4β2R PET 成像 大脑疾病的数量。该提案的目标是检验我们如何发现弱者的陷阱 酸性囊泡中的碱基 α4β2R 配体影响使用 PET 探针的 α4β2R 成像以及使用 PET 探针 成像检查尼古丁如何导致 α4β2R 上调以及伐尼克兰如何改变上调。