A novel PET radiotracer to study 5HT-1A receptors in fetal alcohol exposure

描述（由申请人提供）：产前接触酒精已被证明在整个发育过程中损害大脑中的5-羟色胺（5-HT）系统。该系统的早期损伤与行为异常有关，包括焦虑和攻击性增加。5-HT1A受体在胎儿酒精（FA）暴露中特别受关注，因为它在早期发育中存在，并在5-HT系统和神经内分泌应激轴的调节中发挥作用。在这项工作中，我们建议获得试点数据，以检查产前暴露于酒精引起的5-HT1A受体结合的可能变化。为了实现这一目标，我们将在非人灵长类动物模型中表征和验证一种有前途的新型PET放射配体[F-18]mefway的使用。与目前的5-HT1A放射性配体相比，[F-18]mefway表现出：i)由于[F-18]放射性标记而具有优越的成像特性，ii)在PET信号中改善了靶与背景的结合，以及iii)更有利的代谢物谱以获得定量准确性。[F-18]mefway的体内速率常数将在正常恒河猴中通过一系列多次注射研究进行全面表征，使用动脉血液采样和全室动力学分析。来自第一个特定目标的信息将用于帮助设计实验，以测量产前酒精暴露的恒河猴的5-HT1A受体结合电位，恒河猴属于过去十年在威斯康星大学麦迪逊分校用于研究胎儿酒精暴露的行为，遗传学和神经生物学的动物队列（PI-Schneider: AA12277）。对于第二个具体目标，[F-18]mefway将用于获取产前暴露于酒精和匹配对照的恒河猴的试点数据，以测量体内5-HT1A的结合。然后进行比较，以评估产前酒精暴露对5-HT1A受体系统的影响。了解fa暴露对5-HT1A系统的影响，对于研究fa暴露与神经行为障碍之间关系的中介机制和过程具有很大的潜力。在神经发育过程中，产前暴露于酒精会损害大脑中的5-羟色胺（5-HT）系统。该系统的早期生活损伤与行为异常有关，包括焦虑和攻击性增加，并且可能与胎儿酒精暴露的个体经常表现出的适应不良行为有关。PET神经配体成像是研究胎儿酒精暴露引起的血清素系统体内变化的理想选择。在本提案中，我们的目标是使用一种新型PET放射配体[F-18]mefway在产前酒精暴露动物模型中对5-羟色胺（5-HT1A受体亚型）系统可能的干扰进行初步研究。这项工作具有表征生物标志物的巨大潜力，这将有助于理解胎儿酒精暴露与神经化学损伤之间的关系。

DESCRIPTION (provided by applicant): Prenatal exposure to alcohol has been shown to damage the serotonin (5-HT) system in the brain throughout the course of development. Early life impairment of this system has been linked to behavioral abnormalities including increased anxiety and aggression. The 5-HT1A receptor is of particular interest in fetal alcohol (FA) exposure because of its presence in early development and its role in regulation of the 5-HT system and the neuroendocrine stress axis. In this work, we propose to acquire pilot data to examine possible changes in 5-HT1A receptor binding caused by prenatal exposure to alcohol. To accomplish this, we will characterize and validate the use of a promising, novel PET radioligand, [F-18]mefway, in the nonhuman primate model. Compared with current 5-HT1A radioligands, [F-18]mefway demonstrates: i) superior imaging characteristics due to the [F-18] radiolabel, ii) improved target to background binding in the PET signal, and iii) a more favorable metabolite profile for yielding quantitative accuracy. Full characterization of the in vivo rate constants of [F-18]mefway will be performed in normal rhesus monkeys through a series of multiple injection studies, using arterial blood sampling and full compartmental kinetic analysis. The information from this first specific aim will be used to aid in the design of the experiments to measure 5-HT1A receptor binding potential in prenatally alcohol exposed rhesus monkeys which belong to a cohort of animals that have been used over the last decade at the University of Wisconsin-Madison for studying behavior, genetics and neurobiology in fetal alcohol exposure (PI-Schneider: AA12277). For the second specific aim, [F-18]mefway will be used to acquire pilot data in rhesus monkeys that received prenatal exposure to alcohol and matched controls to measure in vivo 5-HT1A binding. Comparisons will then be performed to evaluate the effects of prenatal alcohol exposure on the 5-HT1A receptor system. An understanding of FA-exposure on the 5-HT1A system holds great potential for examining the mediating mechanisms and processes for relationships between FA-exposure and neurobehavioral impairments. PUBLIC HEALTH RELEVANCE Prenatal exposure to alcohol has been shown to damage the serotonin (5-HT) system in the brain during the course of neural development. Early life impairment of this system has been linked to behavioral abnormalities including increased anxiety and aggression and may be related the maladaptive behaviors often displayed by individuals born with fetal alcohol exposure. PET neuroligand imaging is ideally suited to investigate in vivo changes in the serotonin system caused by fetal alcohol exposure. In this proposal, our goal is to conduct pilot studies of possible disruptions in the serotonin (5-HT1A receptor subtype) system in an animal model of prenatal alcohol exposure using a novel PET radioligand, [F-18]mefway. This work holds great potential for characterizing a biomarker that will aid in understanding the relationships between fetal alcohol exposure and neurochemical impairments.