P2-415: The 5-HT 6 receptor antagonist SUVN-502 enhances acetylcholine and glutamate in rat ventral hippocampus and frontal cortex: A microdialysis study

Abstract

Alzheimer's Disease is associated with deficit in a wide variety of cognitive domains. The 5-HT6 receptor mRNA and protein is distributed widely throughout the CNS, including brain areas associated with cognitive function, such as hippocampus and cerebral cortex. 5-HT6 receptor antagonism can exert cognitive enhancing effects, in part by inducing increase in extracellular levels of acetylcholine and glutamate in hippocampus and cortex. SUVN-502 is identified as a clinical candidate with Ki of 1.71 nM. The effective optimization of critical physico-chemical properties has led to the high oral bioavailability and high brain penetration index. The objective of the present investigation was to examine the effects of SUVN-502 on extracellular levels of acetylcholine and glutamate in rat ventral hippocampus and frontal cortex regions respectively using in vivo brain microdialysis. A guide cannula (CMA/12) was implanted in the rat hippocampus or frontal cortex according to the atlas of Paxinos and Watson. After 48 h, a preequilibrated microdialysis probe was inserted into the guide cannula and was perfused with modified Ringer's solution. A flow rate of 1–2 μL/min and sampling regime of 20 min was employed. After stabilization for 3 h, four stable dialysate samples were collected at basal levels and then animal received oral administration of SUVN-502 (3 and 10 mg/kg) or vehicle. The dialysate samples were collected for period of 360 min. Acetylcholine and glutamate in brain dialysate samples were estimated by validated LC-MS/MS and HPLC-FLU methods. At behaviorally effective doses i.e. 3 and 10 mg/kg, SUVN-502 increased extracellular levels of acetylcholine in dialysates from ventral hippocampus to a maximum of 172 ± 28 and 152 ± 92 % respectively. Where as in case frontal cortex, SUVN-502 (3 and 10 mg/kg) increased extracellular levels of glutamate in dialysates to a maximum of 270 ± 45 and 280 ± 70 % respectively. The present investigation reveals that SUVN-502 could be used to alleviate the cognitive disorders associated with Alzheimer's Disease. SUVN-502 has completed all regulatory safety and toxicity studies to enter to human Phase-I clinical trials in 2008.