title: [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.
authors: Drug Safety Research Labs, Drug Discovery Research, Astellas Pharma Inc., Osaka 532-8514, Japan. takafumi.shirakawa@astellas.com
authors: Takafumi
authors: T
authors: Shirakawa
authors: Keisuke
authors: K
authors: Mitsuoka
authors: Kanae
authors: K
authors: Kuroda
authors: Sosuke
authors: S
authors: Miyoshi
authors: Katsuhisa
authors: K
authors: Shiraki
authors: Hitoshi
authors: H
authors: Naraoka
authors: Akihiro
authors: A
authors: Noda
authors: Akihiko
authors: A
authors: Fujikawa
authors: Michio
authors: M
authors: Fujiwara
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D009474:Neurons / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D015415:Biomarkers; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D019788:Fluorodeoxyglucose F18; D016291:Dizocilpine Maleate; D005947:Glucose