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.