Abstract
395
Objectives: The pathological changes linked to amyotrophic lateral sclerosis (ALS) are glutamatergic neurotoxicity as a result of deficit in glutamate transporter or receptor function and mitochondrial dysfunction as a result of failure in oxidative metabolism. Recent advances in molecular engineering provide a direct link between human ALS disease and gene-modulated animal models, which express a mutation of superoxidase dismutase type 1 (SOD-1) gene. We used rat model of ALS carrying the SOD1 gene mutation to investigate metabotropic glutamate subtype 5 receptors (mGluR5) and glucose metabolism. Methods: PET imaging studies (MicroPET P4, Concord Microsystems) were conducted of mGluR5 function with [11C]M-PEPy (3-methoxy-5- [(2-pyridyl)ethyl] pyridine) and glucose metabolism with [18F]FDG in 4 ALS rats and 4 age matched control Sprague Dawley rats. Anesthetized (1-1.5% isoflurane, 2% nitrous oxide and oxygen flow of 1 L/min) rats were injected in the camera with mGluR5 ligand (37MBq) or with [18F]FDG (15 MBq) and the volumetric dynamic data were acquired for an hour. In these preliminary studies accumulation was determined in standard unit values in time interval 5-20 min for [11C]M-PEPy and 40-60 min for [18F]FDG. Results: In the ALS rats mGluR5 expression was significantly enhanced in the spinal cord as well as in several brain areas related to motor function compared to the control rats. Glucose metabolism was also enhanced in the ALS rats in the spinal cord. However, glucose metabolism was decreased in cortical areas, especially in the cingulate cortex. Conclusions: These preliminary studies are the first in vivo studies to show glutamatergic function in the ALS–like degeneration. Since, Riluzole, the only approved drug for ALS is based on glutamatergic responses, it is obvious that PET imaging of glutamate receptors could provide invaluable information for drug development.
Research Support (if any): NIH-NIBIB R01-EB001850
- Society of Nuclear Medicine, Inc.