PET imaging of a4b2 nicotinic receptor upregulation and smoking cessation

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α4β2型 烟碱乙酰胆碱受体（α4β 2 Rs）。长期尼古丁暴露增加高亲和力α4β 22 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 这个提议是基于我们最近的发现，α4β 2 R配体是弱碱，如吸烟 终止剂伐伦克林（Chantix），可选择性地捕获在含α4β 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α4β 2 R的酸性 囊泡尼古丁也是一种弱碱，由于其配体pKa和对α4β 22 Rs的亲和力较低，因此未被捕获 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α4β 22 R PET探针的潜在细胞分布的新信息，所有这些都是 是薄弱的基础。与伐尼克兰和尼古丁一样，不同的α4β 2 R PET探针具有不同的配体pKas， 对α4β 2 Rs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。 虽然许多研究使用了对脑中α4β 22 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。利用我们关于α4β 2 R弱碱配体在 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 说明α4β 2 R配体在酸性囊泡中的捕获。PET具有更广泛的应用前景 由于α4β 2 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α4β 2 R配体影响PET探针对α4β 2 R的成像， 成像以检查尼古丁如何引起α4β 2 R上调以及伐尼克兰如何改变上调。

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 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.