Using in-vivo Real-time Biosensor to Evaluate Prodrugs Designed to Prolong Therapeutic Effects for Smoking Cessation.

摘要 针对中枢神经系统(CNS)的药物开发受到阻碍，因为无法直接在 活体临床前测量。在这里，我们建议通过以下方式确定最佳戒烟药物候选 监测我们新合成的前体药物如何改变大脑对尼古丁的实时多巴胺反应。 Varenicline(Chantix®)是FDA批准的用于戒烟的领先口服药物。然而，只有 22%的患者在接受varenicline治疗后持续戒烟52周，67%的患者停止戒烟 治疗过早，提示需要患者依从性更好的治疗。要解决这个问题 需要，我们最近开发了缓释前药，旨在改善药代动力学 伐伦克林的性质。Varenicline通过双重作用减少尼古丁的渴求和使用：首先提供短暂的 增加多巴胺水平，随后通过阻断多巴胺对尼古丁3-5的反应。这些 这些变化旨在稳定大脑中的多巴胺信号，以实现两个目标：(1)减少 短暂增加多巴胺和(2)延长药物降低奖励价值的持续时间 尼古丁。在这个第一阶段的资助中，我们将使用体内的多巴胺生物传感器来评估实时的多巴胺水平 在服用我们的新型前体药物后，纹状体(大脑中的一个奖励中心)。我们将建立 脑功效(根据多巴胺释放的定义)与循环中药物水平之间的体内关系。 这些研究将使我们能够筛选出在改变血药浓度和血药浓度方面具有最佳疗效的前药。 多巴胺反应的持续时间，我们将其作为预测戒烟疗效的生物标志物。 这项第一阶段拨款的主要假设是，一种稳定体内初始多巴胺释放的前药 纹状体虽然也更有效地阻断随后对尼古丁的多巴胺反应，但也会更有效 在减少静脉注射尼古丁的自我给药方面优于varenicline。我们将通过以下方式检验这一假设：1)建立 每种前药相对于伐伦尼克林的药代动力学；2)使用实时测量纹状体多巴胺水平 体内生物传感器，以确定不同的暴露曲线如何影响多巴胺反应；以及3)评估 使用已建立的尼古丁成瘾模型对前药反应的行为变化。我们最初的 试验数据表明，与varenicline相比，我们的前药有利于改变多巴胺的释放。 纹状体的侧写。因此，我们的前药方法改变了奖励系统的生理功能。 可能是一种更好的临床用药。重要的是，这笔赠款中使用的核心技术 改进后的戒烟药物可以更广泛地作为一种通用的药效学测定方法。 中枢神经系统药物开发。因此，本研究将为利用体内真实药物发现药物提供一个平台。 时间方法论。SpaceRx拥有制造varenicline类似物和前药的丰富经验，并且实际- 时间生物传感和测量神经活动动力学是贝特利实验室的核心技术，使 我们的团队非常适合测试我们的假设，成功地开发出新型戒烟药物。

ABSTRACT Developing drugs that target the central nervous system (CNS) is hampered by an inability to perform direct in vivo preclinical measurements. Here, we propose to identify an optimal smoking cessation drug candidate by monitoring how our newly synthesized prodrugs alter real-time brain dopamine responses to nicotine. Varenicline (CHANTIX®) is the leading FDA-approved oral medication for smoking cessation. However, only 22% of patients maintain abstinence for 52 weeks following varenicline treatment1 and 67% of patients stop treatment prematurely2, suggesting that therapies with better patient compliance are needed. To address this need, we recently developed extended-release prodrugs that are designed to improve the pharmacokinetic properties of varenicline. Varenicline reduces nicotine craving and use by dual action: first providing a transient increase in dopamine levels and subsequently by blocking the dopamine response to nicotine3-5. These changes aim to stabilize dopamine signaling in the brain to achieve two goals: (1) reduce the side effects of transiently dopamine increases and (2) prolong the duration with which the drug reduces the reward value of nicotine. In this Phase I grant, we will use an in vivo dopamine biosensor to evaluate real-time dopamine levels in the striatum (a reward center in the brain) following administration of our novel prodrugs. We will establish an in vivo relationship between brain efficacy (as defined by dopamine release) and drug levels in circulation. These studies will allow us to screen for prodrugs that have optimal efficacy for altering both the level and duration of dopamine response, which we use as a biomarker for predicting efficacy for smoking cessation. The primary hypothesis of this Phase I grant is that a prodrug that stabilizes the initial dopamine release in the striatum while also more efficiently blocking subsequent dopamine responses to nicotine will be more effective than varenicline at decreasing IV self-administration of nicotine. We will test this hypothesis by: 1) establishing pharmacokinetics for each prodrug relative to varenicline; 2) measuring striatal dopamine levels using real-time in vivo biosensors to determine how different exposure curves affect dopamine response; and 3) assessing behavioral changes in response to the prodrugs using a well-established nicotine addiction model. Our initial pilot data demonstrate that, in comparison to varenicline, our prodrugs favorably alter the dopamine release profile in the striatum. Thus, our prodrug approach changes the physiological function of the reward system and may be a better drug for clinical use. Importantly, the core technology used in this grant to develop improved smoking cessation drugs can be utilized more broadly as a general pharmacodynamic assay for CNS drug development. Therefore, this research will provide a platform for drug discovery using in vivo real- time methodologies. SpaceRx has extensive experience making varenicline analogs and prodrugs, and real- time biosensing and measuring neural activity dynamics is a core technology of the Betley laboratory, making our team ideally suited to test our hypothesis to successfully develop novel smoking cessation drugs.