In Vivo Evaluation of [11C]DASB for Quantitative SERT Imaging in Rats and Mice

Serotonin (5-HT) plays a key role in the central nervous system and is involved in many essential neurological processes, such as mood, social behavior and sleep. The serotonin transporter ligand [¹¹C]DASB has been used to determine the binding potential (BPND), which is the ratio of available transporter sites (Bavail) and radioligand affinity (1/appKD) under in vivo conditions. Due to the increasing number of animal models of human diseases, there is a pressing need to evaluate the applicability of [¹¹C]DASB to rats and mice. Here, we assessed the feasibility of using [¹¹C]DASB for the quantification of SERT density and affinity in vivo in rats and mice. Rats and mice underwent a total of 4 PET scans with increasing doses of the unlabeled ligand to calculate Bavail and appKD using the multiple ligand concentration transporter assay. An additional PET scan was performed to calculate test-retest reproducibility and reliability. The BPND was calculated using the simplified reference tissue model (SRTM) and the results obtained using different reference regions were compared. Displaceable binding of [¹¹C]DASB was found in all brain regions of the rats and mice, with the highest binding in the thalamus and lowest binding in the cerebellum. In rats, displaceable binding was largely reduced in the cerebellar cortex, which was spatially indistinguishable from the cerebellar white matter in the mice. Using the cerebellum with fully saturated binding sites as the reference region did not lead to reliable results. Test–retest reproducibility in the thalamus was > 90 % in the mice and rats. In the rats, Bavail, appKD and ED50 were 3.9 ± 0.4 pmol/mL, 2.2 ± 0.4 nM and 12.0 ± 2.6 nmol/kg, respectively, while analysis of the mouse measurements resulted in inaccurate fits due to the high injected tracer mass. Our data show that [¹¹C]DASB can be used to quantify 5 HT transporter (SERT) density in rats with good reproducibility. The BPND values were in agreement with the distribution of the SERT in the rat brain. It remains difficult to estimate accurate and quantitative parameters from mouse measurements due to the high injected tracer mass and underestimation of the binding parameters due to high displaceable binding in the reference region.

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