title: Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using 18F-GE-179 and 18F-GE-194 Autoradiography.
abstract: In vivo imaging of N-methyl-d-aspartate (NMDA) glutamate receptor and γ-aminobutyric acid (GABA)-A receptor during progression of brain pathology is challenging because of the lack of imaging tracers with high affinity and specificity.
  
  
  
  We monitored changes in NMDA receptor and GABA-A receptor in a clinically relevant model of traumatic brain injury (TBI) induced by lateral fluid percussion in adult rats, using 2 new ligands for PET: (18)F-GE-179 for the open/active state of the NMDA receptor ion channel and (18)F-GE-194 for GABA-A receptor. Ex vivo brain autoradiography of radioligands was performed at subacute (5-6 d) and chronic (40-42 d) time points after TBI.
  
  
  
  At 5-6 d after TBI, (18)F-GE-179 binding was higher in the cortical lesion area, in the lesion core, and in the hippocampus than in the corresponding contralateral regions; this increase was probably related to increased permeability of the blood-brain barrier. At 40-42 d after TBI, (18)F-GE-179 binding was significantly higher in the medial cortex, in the corpus callosum, and in the thalamus than in the corresponding contralateral regions. Five to 6 days after TBI, (18)F-GE-194 binding was significantly higher in the lesion core and significantly lower in the ipsilateral thalamus. By 40-42 d after TBI, the reduction in (18)F-GE-194 binding extended to the cortical lesion, including the perilesional cortex around the lesion core. The reduction in thalamic binding was more extensive at 40-42 d than at 5-6 d after TBI, suggesting a progressive decrease in thalamic GABA-A receptor density. Immunohistochemistry against GABA-A α1 subunit revealed a similar decrease to (18)F-GE-194 binding, particularly during the chronic phase.
  
  
  
  Our data support the validity of novel (18)F-GE-179 and (18)F-GE-194 radioligands for the detection of changes in active NMDA receptor and GABA-A receptor in the injured brain. These tools are useful for follow-up evaluation of secondary postinjury pathologies.
authors.affiliation: PET Preclinical Laboratory, Turku PET Centre, University of Turku, Turku, Finland Medicity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Francisco
authors.initials: F
authors.lastname: López-Picón
authors.affiliation: PET Preclinical Laboratory, Turku PET Centre, University of Turku, Turku, Finland Medicity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Anniina
authors.initials: A
authors.lastname: Snellman
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Olena
authors.initials: O
authors.lastname: Shatillo
authors.affiliation: Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Lehtiniemi
authors.affiliation: PET Preclinical Laboratory, Turku PET Centre, University of Turku, Turku, Finland Medicity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Tove J
authors.initials: TJ
authors.lastname: Grönroos
authors.affiliation: PET Preclinical Laboratory, Turku PET Centre, University of Turku, Turku, Finland Medicity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Marjamäki
authors.affiliation: GE Healthcare Life Sciences, Amersham, Buckinghamshire, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Trigg
authors.affiliation: GE Healthcare Life Sciences, Amersham, Buckinghamshire, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Jones
authors.affiliation: Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland Accelerator Laboratory, Åbo Akademi University, Turku, Finland; and Department of Chemistry, University of Turku, Turku, Finland.
authors.forename: Olof
authors.initials: O
authors.lastname: Solin
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Asla
authors.initials: A
authors.lastname: Pitkänen
authors.affiliation: PET Preclinical Laboratory, Turku PET Centre, University of Turku, Turku, Finland Medicity Research Laboratory, University of Turku, Turku, Finland mehaaso@utu.fi.
authors.forename: Merja
authors.initials: M
authors.lastname: Haaparanta-Solin
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D000070642:Brain Injuries, Traumatic / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D057054:Molecular Imaging / Q000379:methods*; D009928:Organ Specificity; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate
keywords: GE-179; GE-194; N-methyl-aspartic acid receptor; traumatic brain injury; γ-aminobutyric acid receptor A