[18F]FDG-PET as an Imaging Biomarker to NMDA Receptor Antagonist-Induced Neurotoxicity

Abstract

Positron emission tomography (PET) is an effective tool for noninvasive examination of the body and provides a range of functional information. PET imaging with [(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) has been used to image alterations in glucose metabolism in brain or cancer tissue in the field of clinical diagnosis but not in the field of toxicology. A single dose of N-methyl-d-aspartate (NMDA) receptor antagonist induces neuronal cell degeneration/death in the rat retrosplenial/posterior cingulate (RS/PC) cortex region. These antagonists also increase local cerebral glucose utilization. Here, we examined the potential of [(18)F]FDG-PET as an imaging biomarker of neurotoxicity induced by an NMDA receptor antagonist, MK-801. Using [(18)F]FDG-PET, we determined that increased glucose utilization involved the neurotoxicity induced by MK-801. The accumulation of [(18)F]FDG was increased in the rat RS/PC cortex region showing neuronal cell degeneration/death and detected before the onset of neuronal cell death. This effect increased at a dose level at which neuronal cell degeneration recovered 24h after MK-801 administration. Scopolamine prevented the neurotoxicity and [(18)F]FDG accumulation induced by MK-801. Furthermore, in cynomolgus monkeys that showed no neuronal cell degeneration/death when treated with MK-801, we noted no differences in [(18)F]FDG accumulation between test and control subjects in any region of the brain. These findings suggest that [(18)F]FDG-PET, which is available for clinical trials, may be useful in generating a predictive imaging biomarker for detecting neurotoxicity against NMDA receptor antagonists with the same pharmacological activity as MK-801.

Functional imaging of pharmacological action of SGLT2 inhibitor ipragliflozin via PET imaging using 11C‐MDG

“…PET scanning was performed using Siemens microPET scanners (Siemens, Munich, Germany) as described previously with some modification (Shirakawa et al. ; Kaneko et al. ).…”

“…In the 18 F‐fluorodeoxyglucose ( 18 F‐FDG) PET study, synthesis of 18 F‐FDG was carried out as described previously (Shirakawa et al. ; Kaneko et al. ).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…This finding later opened the idea of glutamatergic model of schizophrenia in the past two decades (Javitt and Zukin, 1991;Javitt et al, 2012). NMDAR antagonists have neuroprotective effects, but they also have proven neurotoxic effects in rodents, although their effects on nonhuman primates and humans are still unclear (Low and Roland, 2004;Shirakawa et al, 2013;Wang et al, 2013a). Much effort has been put in to identify the putative mechanisms of NMDAR antagonist-induced neuroplasticity .…”

“…The MK-801-induced toxicity in adult rats can be prevented by injections of scopolamine and NBQX (6-nitro-2,3-dioxo-1,4-dihydrobenzo[f]quinoxaline-7-sulfonamide) (into the cerebral cortex) and clonidine (into basal forebrain) and by systemic scopolamine (Shirakawa et al, 2013), erythropoietin (partial effect, counteracting the reduction in BDNF and GNDF expression by NMDAR antagonists) (Dzietko et al, 2004), and ethanol (Farber et al, 2004), but not by increased BDNF (Vaisanen et al, 2003). Neurotoxicity by PCP and ketamine can also be attenuated by diazepam and haloperidol (Nakao et al, 1996;Nakki et al, 1996).…”

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

“…The response to NDMA receptor agonists has been monitored by PET using [ 18 F]FDG. 76 No PET radioligands developed for this receptor have been suitable for clinical use, 77 though it has been investigated with SPECT. 78 …”