MicroPET/CT Imaging of [¹⁸F]-FEPPA in the Nonhuman Primate: A Potential Biomarker of Pathogenic Processes Associated with Anesthetic-Induced Neurotoxicity

Abstract

Background. The inhalation anesthetics nitrous oxide (N 2 O) and isoflurane (ISO) are used in surgical procedures for human infants. Injury to the central nervous system is often accompanied by localization of activated microglia or astrocytosis at the site of injury. The tracer that targets to the peripheral benzodiazepine receptor (PBR), [ 18 F]N-2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([ 18 F]-FEPPA), has been reported as a sensitive biomarker for the detection of neuronal damage/inflammation. Methods. On postnatal day (PND) 5 or 6 rhesus monkey neonates were exposed to a mixture of N 2 O/oxygen and ISO for 8 hours and control monkeys were exposed to room air. MicroPET/CT images with [ 18 F]-FEPPA were obtained for each monkey 1 day, one week, three weeks, and 6 months after the anesthetic exposure. Results. The radiotracer quickly distributed into the brains of both treated and control monkeys on all scan days. One day after anesthetic exposure, the uptake of [ 18 F]-FEPPA was significantly increased in the temporal lobe. One week after exposure, the uptake of [ 18 F]-FEPPA in the frontal lobe of treated animals was significantly greater than that in controls. Conclusions. These findings suggest that microPET imaging is capable of dynamic detection of inhaled anesthetic-induced brain damage in different brain regions of the nonhuman primate.

In Vivo Monitoring of Sevoflurane-induced Adverse Effects in Neonatal Nonhuman Primates Using Small-animal Positron Emission Tomography

“…[36][37][38] We have developed a microPET protocol to investigate possible neurotoxic effects associated with developmental exposures to sevoflurane in vivo using imaging approaches. 7,[39][40][41][42][43] in the cnS, translocator proteins (TSPOs, 18 Kda), previously known as peripheral benzodiazepine receptors, are primarily located in glial cells, and their levels are believed to increase in areas of neuronal injury after exposure to neurotoxicants. 44,45 Therefore, they are widely recognized as important targets for PET imaging.…”

“…nonhuman primate models are thought to be more relevant than rodent models because of their similarities to human beings in regard to the length of pregnancy, brain neuroanatomical organization, and pharmacodynamics after the administration of anesthetics, and we have used these models in previous studies. 41,[48][49][50] in the current study, noninvasive monitoring of physiologic parameters in neonatal monkeys was utilized to evaluate whether homeostasis in the exposed animals was within the normal range during anesthesia.…”

The Utility of a Nonhuman Primate Model for Assessing Anesthetic-Induced Developmental Neurotoxicity

“…The thin sections were then counter-stained with uranyl acetate and lead citrate and randomly selected fields were examined at 100 kV using a Jeol-2100 electron microscope. [16]. Briefly, anesthetized neonates were placed in the prone position and maintained under general anesthesia via inhalation of 1.5% isoflurane plus oxygen through a customized mask throughout the two-hour microPET scans.…”

“…Nonhuman primate models are thought to be more relevant than rodent models because of their similarities to human beings in regards to the length of pregnancy, brain neuroanatomical organization, and pharmacodynamics following the administration of anesthetics [14] and these models have been used in previous studies [15,16,17]. In the current study, minimally invasive monitoring of physiological parameters in neonatal monkeys was utilized throughout the exposures such that it was possible to evaluate whether physiological homeostasis in the exposed animals was significantly affected during anesthesia.…”

“…Therefore, neuroinflammatory changes in the central nervous system (CNS) can be regarded as measures of anesthetic effects as well. Micro-positron emission tomography (microPET) imaging using a radiolabeled ligand specific to activated microglia and astrocytes to detect the occurrence of active inflammatory processes has been used to monitor such processes [16]. Nevertheless, markers of neurotoxicity that can be observed in readily accessible bodily fluids have long been sought [22,23].…”