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

一种新型 PET 放射性示踪剂，用于研究胎儿酒精暴露中的 5HT-1A 受体

• 批准号: 7510115
• 负责人: Bradley T Christian
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7510115
• 关键词: Aggressive behavior; Alcohols; Animal Model; Animals; Anorexia Nervosa; Anxiety; Anxiety Disorders; Behavior; Behavioral; Behavioral Genetics; Binding; Biological Assay; Biological Markers; Bipolar Depression; Birth; Blood; Blood specimen; Brain; Characteristics; Control Groups; Data; Development; Disruption; Dissociation; Experimental Designs; Fetal Alcohol Exposure; Future; Goals; Human; Image; Impairment; Individual; Injection of therapeutic agent; Kinetics; Knowledge; Life; Link; Macaca mulatta; Major Depressive Disorder; Measurement; Measures; Mediating; Methods; Modeling; Monkeys; Neurobiology; Neurosecretory Systems; Panic Disorder; Parents; Pilot Projects; Plasma; Play; Positron-Emission Tomography; Preparation; Primates; Process; Protocols documentation; Public Health; Radiolabeled; Rate; Regulation; Reporting; Research Personnel; Resources; Role; Sampling; Scanning; Sensory Receptors; Series; Serotonin; Serotonin Receptor 5-HT1A; Serotonin Receptor 5-HT2A; Signal Transduction; Stress; Support System; System; Tissues; Universities; Wisconsin; Work; alcohol exposure; cohort; design; fetal; improved; in vivo; interest; molecular imaging; neurobehavioral; neurochemistry; neurodevelopment; nonhuman primate; novel; postsynaptic; prenatal exposure; radiochemical; radioligand; radiotracer; receptor; receptor binding; receptor density; research study; response; social; tool

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.

描述（由申请人提供）：在整个发育过程中，已经显示出在酒精产前暴露于酒精的大脑中的5-羟色胺（5-HT）系统。该系统的早期生命障碍与行为异常有关，包括增加焦虑和攻击性。 5-HT1A受体在胎儿酒精（FA）暴露中特别感兴趣，因为它在早期发育及其在调节5-HT系统和神经内分泌应力轴上的作用。在这项工作中，我们建议获取试点数据，以检查由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，我们将在非人类灵长类动物模型中表征和验证使用有希望的新型PET放射线[F-18] Mefway。与当前的5-HT1A放射线配体相比，[F-18] Mefway证明了：i）由于[F-18] radiolabel，ii）提高了对PET信号中背景结合的靶标的卓越成像特性，而III）更有利的代谢物谱，以产生定量准确性。 [F-18] Mefway的体内速率常数的全面表征将通过一系列多次注射研究在正常的恒河猴中进行，并使用动脉血液采样和全部分室动力学分析进行。第一个特定目标的信息将用于帮助设计实验，以测量饮酒的5-HT1A受体结合潜力，暴露于产前暴露的恒河猴猴子，这些猴子属于过去十年在威斯康星大学 - 维斯康星大学 - 麦迪逊分校用于研究行为，遗传学和神经生物学曝光中的一系列动物。对于第二个特定目的，[F-18] Mefway将用于在恒河猴中获取试验数据，这些猴子接收了产前暴露于酒精和匹配的对照中，以测量体内5-HT1A结合。然后将进行比较，以评估产前酒精暴露对5-HT1A受体系统的影响。对5-HT1A系统FA暴露的理解具有检查FA暴露与神经行为损伤之间关系的中介机制和过程的巨大潜力。在神经发育过程中，已经显示出产前暴露于酒精的公共卫生相关性会损害大脑中的5-羟色胺（5-HT）系统。该系统的早期生活障碍与行为异常有关，包括焦虑和攻击性的增加，并且可能与受胎儿酒精暴露的人经常表现出的适应不良行为有关。 PET神经群成像非常适合研究由胎儿酒精暴露引起的5-羟色胺系统的体内变化。在此提案中，我们的目标是对使用新型的PET放射性物体[F-18] Mefway进行动物模型中5-羟色胺（5-HT1A受体亚型）系统可能中断的试点研究。这项工作具有表征生物标志物的巨大潜力，该标志物将有助于理解胎儿酒精暴露与神经化学障碍之间的关系。