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）：产前接触酒精已被证明会在整个发育过程中损害大脑中的血清素（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，因为它存在于早期发育中，并且在调节 5-HT 系统和神经内分泌应激轴中发挥作用。在这项工作中，我们建议获取试点数据来检查产前接触酒精引起的 5-HT1A 受体结合可能发生的变化。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并验证一种有前途的新型 PET 放射性配体 [F-18]mefway 的使用。与当前的 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异的成像特性，ii) 改进了 PET 信号中的目标与背景结合，以及 iii) 更有利的代谢物配置文件以产生定量精度。 [F-18]mefway 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恒河猴中进行，使用动脉血采样和全室动力学分析。第一个具体目标的信息将用于帮助设计实验，测量产前酒精暴露的恒河猴的 5-HT1A 受体结合潜力，恒河猴属于过去十年在大学使用的一组动物威斯康星-麦迪逊分校研究胎儿酒精暴露的行为、遗传学和神经生物学（PI-Schneider：AA12277）。对于第二个具体目标，[F-18]mefway 将用于获取恒河猴的初步数据，这些恒河猴在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。了解 5-HT1A 系统上的 FA 暴露对于检查 FA 暴露与神经行为损伤之间关系的中介机制和过程具有巨大的潜力。公共卫生相关性 产前接触酒精已被证明会在神经发育过程中损害大脑中的血清素 (5-HT) 系统。该系统的早期损害与行为异常有关，包括焦虑和攻击性增加，并且可能与出生时胎儿酒精暴露的个体经常表现出的适应不良行为有关。 PET 神经配体成像非常适合研究胎儿酒精暴露引起的体内血清素系统变化。在本提案中，我们的目标是使用新型 PET 放射性配体 [F-18]mefway，在产前酒精暴露的动物模型中进行血清素（5-HT1A 受体亚型）系统可能破坏的初步研究。这项工作在表征生物标志物方面具有巨大的潜力，有助于了解胎儿酒精暴露与神经化学损伤之间的关系。