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.

摘要 烟草在世界范围内继续被广泛使用，主要是通过吸烟，并且是导致肥胖的主要原因。 在美国可预防的死亡烟草使用是由尼古丁成瘾驱动的，尼古丁成瘾始于尼古丁 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α 4 β 2型上， 烟碱型乙酰胆碱受体（NAT 4-NAT 2 Rs）。长期尼古丁暴露增加高亲和力β 4 β 2 R结合 大脑中的一个位点，一个被称为“上调”的过程，与尼古丁成瘾的渴望和戒断有关。这 该建议是基于我们最近的发现，即作为弱碱的β 4 β 2 R配体，如吸烟 终止试剂伐伦克林（Chantix），可选择性地捕获在含β 4 β 2 R的细胞酸性囊泡中 和神经元。捕获的伐尼克兰的缓慢释放降低了尼古丁上调的影响。选择性 尼古丁上调进一步调节捕获，这增加了含β 4 β 2 R的酸性磷酸酶的数量。 囊泡尼古丁也是一种弱碱，由于其配体pKa和对β 4 β 2 Rs的亲和力较低，因此不会被捕获 比伐伦克林的效果更好。这些结果为伐尼克兰如何引起戒烟提供了一个新的范例。 它们还提供了关于PET探针的潜在细胞分布的新信息，所有这些都 是弱碱。与伐尼克兰和尼古丁一样，不同的β 4 β 2 R PET探针具有不同的配体pKas， 对α 4 β 2 R的亲和力，这解释了动力学的差异，伐尼克兰和尼古丁的可置换结合， 不可替代的结合和代谢。 虽然许多研究已经使用了对脑中的β 4 β 2 R高亲和力结合位点特异性的PET探针，但这些研究表明， 结合和结合动力学的解释使研究复杂化， 和/或伐尼克兰存在。利用我们的概念，捕获的α 4 β 2 R弱碱配体， 细胞内的酸性囊泡，我们将开发新的细胞和整体模型的PET探针动力学，考虑到 考虑到在酸性囊泡中的配体捕获。PET具有更广泛的应用前景 方法，将在本申请中开发，因为对于204 - 202 R PET成像目前正在进行中， 大脑紊乱的数量。这个提议的目的是研究我们如何发现 酸性囊泡中的碱基β 4 β 2 R配体影响使用PET探针的β 4 β 2 R成像， 成像以检查尼古丁如何引起β 4 β 2 R上调以及伐尼克兰如何改变上调。