title: In vivo imaging of system xc- as a novel approach to monitor multiple sclerosis.
abstract: OBJECTIVE
  Glutamate excitotoxicity contributes to oligodendroglial and axonal damage in multiple sclerosis pathology. Extracellular glutamate concentration in the brain is controlled by cystine/glutamate antiporter (system xc-), a membrane antiporter that imports cystine and releases glutamate. Despite this, the system xc(-) activity and its connection to the inflammatory reaction in multiple sclerosis (MS) is largely unknown.
  
  
  METHODS
  Longitudinal in vivo magnetic resonance (MRI) and positron emission tomography (PET) imaging studies with 2-[(18)F]Fluoro-2-deoxy-D-glucose ([(18)F]FDG), [(11)C]-(R)-(1-(2-chlorophenyl)-N-methyl-N-1(1-methylpropyl)-3-isoquinolinecarboxamide ([(11)C]PK11195) and (4S)-4-(3-(18)F-fluoropropyl)-L-glutamate ([(18)F]FSPG) were carried out during the course of experimental autoimmune encephalomyelitis (EAE) induction in rats.
  
  
  RESULTS
  [(18)F]FSPG showed a significant increase of system xc(-) function in the lumbar section of the spinal cord at 14 days post immunization (dpi) that stands in agreement with the neurological symptoms and ventricle edema formation at this time point. Likewise, [(18)F]FDG did not show significant changes in glucose metabolism throughout central nervous system and [(11)C]PK11195 evidenced a significant increase of microglial/macrophage activation in spinal cord and cerebellum 2 weeks after EAE induction. Therefore, [(18)F]FSPG showed a major capacity to discriminate regions of the central nervous system affected by the MS in comparison to [(18)F]FDG and [(11)C]PK11195. Additionally, clodronate-treated rats showed a depletion in microglial population and [(18)F]FSPG PET signal in spinal cord confirming a link between neuroinflammatory reaction and cystine/glutamate antiporter activity in EAE rats.
  
  
  CONCLUSIONS
  Altogether, these results suggest that in vivo PET imaging of system xc(-) could become a valuable tool for the diagnosis and treatment evaluation of MS.
authors.affiliation: Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain. amartin@cicbiomagune.es.
authors.forename: Abraham
authors.initials: A
authors.lastname: Martín
authors.affiliation: Department of Neurosciences, University of the Basque Country, Barrio Sarriena s/n, 48940, Leioa, Spain.|Achucarro Basque Center for Neuroscience, UPV/EHU, 48170, Zamudio, Spain.|Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940, Leioa, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Vázquez-Villoldo
authors.affiliation: Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.|Radiochemistry and Nuclear Imaging, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gómez-Vallejo
authors.affiliation: Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.|Magnetic Resonance Imaging, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Padro
authors.affiliation: Department of Neurosciences, University of the Basque Country, Barrio Sarriena s/n, 48940, Leioa, Spain.|Achucarro Basque Center for Neuroscience, UPV/EHU, 48170, Zamudio, Spain.|Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940, Leioa, Spain.
authors.forename: Federico N
authors.initials: FN
authors.lastname: Soria
authors.affiliation: Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.
authors.forename: Boguslaw
authors.initials: B
authors.lastname: Szczupak
authors.affiliation: Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.|Magnetic Resonance Imaging, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Plaza-García
authors.affiliation: Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Arrieta
authors.affiliation: Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.|Magnetic Resonance Imaging, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.
authors.forename: Torsten
authors.initials: T
authors.lastname: Reese
authors.affiliation: Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.|Radiochemistry and Nuclear Imaging, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Llop
authors.affiliation: Department of Neurosciences, University of the Basque Country, Barrio Sarriena s/n, 48940, Leioa, Spain.|Achucarro Basque Center for Neuroscience, UPV/EHU, 48170, Zamudio, Spain.|Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940, Leioa, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Domercq
authors.affiliation: Department of Neurosciences, University of the Basque Country, Barrio Sarriena s/n, 48940, Leioa, Spain. carlos.matute@ehu.es.|Achucarro Basque Center for Neuroscience, UPV/EHU, 48170, Zamudio, Spain. carlos.matute@ehu.es.|Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940, Leioa, Spain. carlos.matute@ehu.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002552:Cerebral Ventricles / Q000000981:diagnostic imaging / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D064847:Multimodal Imaging; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009929:Organ Size; D049268:Positron-Emission Tomography; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D027182:Amino Acid Transport System y+
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D002352:Carrier Proteins; D005947:Glucose; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; C000723960:Slc7a11 protein, rat; D027182:Amino Acid Transport System y+
keywords: Multiple sclerosis; PET; T1W-MRI; [11C]PK11195; [18F]FDG; [18F]FSPG