PET imaging of a4b2 nicotinic receptor upregulation and smoking cessation

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42型 烟碱型乙酰胆碱受体(42RS)。长期尼古丁暴露增加高亲和力42R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42R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42R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42R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42RS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42RPET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42RPET探针具有不同的配体pKas和 42RS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42R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42R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42RPET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42R上调以及varenicline如何改变上调。

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.