Description
Objectives: The sigma-1 receptor, a unique orphan receptor, is strongly expressed in neurons and glia. Sigma-1 receptors are implicated in cellular differentiation, neuroplasticity, neuroprotection, and cognition 1. Sigma-1 agonists are potentially useful in the treatment of neurodegenerative diseases, stroke, and depression. PET studies of sigma-1 receptors have been performed in primate brain but not in the aging brain of rodents. Quantification of sigma-1 receptors in rat brain is of interest for the study of animal models of human disease and for the study of mechanisms of action of sigma-1 ligands. The aim of this study was to quantify sigma-1 receptors in rat brain using the agonist radiotracer 11C-SA4503 and microPET.Methods: Sigma-1 receptors in young (6 weeks), middle aged (16-18 months) and aged (24 months) Wistar Hannover rats were visualized using 11C-SA4503. A canula placed in a femoral artery was used for blood sampling. The time-dependent uptake of 11C-SA4503 in rat brain was measured using a Siemens/Concorde microPET Focus 220 camera, and various tracer-kinetic
models were fitted to this data, using plasma radioactivity as input function. Radioactive metabolites in plasma were quantified using reversed-phase HPLC. A biodistribution study was also performed.
Results: Aged and middle aged rats metabolised 11C-SA4503 to a significantly lesser extent than the young rats. Apparent distribution volume (from Logan plots) calculated with the uncorrected plasma values as input, did not show any significant difference between the young, middle aged and aged rats. However, when the same was calculated using plasma input corrected for metabolites, middle aged and aged rats showed a significant reduction in the apparent distribution volume in the entire brain. In the biodistribution study, the aged animals showed region specific differences in the uptake of 11C-SA4503: cerebral cortex in the aged rats had a significantly higher uptake, cerebellum had a non significant increase and rest of the brain had a non significant decrease. Therefore, the scan data is now being further evaluated to quantify regional distribution volumes of 11C-SA4503.
Conclusions: Results indicate that sigma-1 receptors are quantifiable as the distribution volume of 11C-SA4503 (from a Logan plot) in rats. Further, metabolite correction of the plasma input function has a large impact on the calculated distribution volume; therefore this correction seems essential. Biodistribution studies indicate regional differences in the brain. This method
of sigma-1 receptor quantification can now be used, in conjunction with behavioural or lesion methods, to study sigma receptors in animal models of neuropsychiatric disorders and also to evaluate sigma ligands in these animal models.
| Periode | mei-2011 |
|---|---|
| Evenementstitel | International Conference of Quantification of Brain Function with PET |
| Evenementstype | Conference |
| Locatie | Barcelona, SpainToon op kaart |