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

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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.