Binding of the non-peptide vasopressin V-1a receptor antagonist SR-49059 in the rat brain: An in vitro and in vivo autoradiographic study

A potent non-peptide vasopressin (AVP) antagonist, SR-49059, displaying hig h stability and selective affinity for the V-1a AVP receptor subtype, has r ecently been described. The objective of this study was to assess the bindi ng properties and the penetrability of this compound in the rat brain. Both in vitro and in vivo binding autoradiography experiments were performed. I n all studies, the liver was used as a reference V-1a tissue. In vitro labe lling of rat brain sections with [H-3]SR-49059 was similar to that previous ly detected with [H-3]AVP, which confirms that the majority of central AVP binding sites are V-1a sites similar to peripheral V-1a receptors. As expec ted, intense specific labelling occurred mainly in the lateral septum, the fundus striatum, the hypothalamic stigmoid nucleus and the area postrema-nu cleus of the solitary tract complex. In vivo binding autoradiography showed that [H-3]SR-49059 injected intravenously did not enter the brain parenchy ma. Specific labelling was however clearly detectable in brain regions with permeable hematoencephalic barrier, the choroid plexus and other circumven tricular organs expressing V-1a receptors, namely the subfornical organ, th e pineal gland and the area postrema. The specificity of [H-3]SR-49059 bind ing in the latter structures was confirmed by the fact that labelling was p revented by pretreatment of animals with high doses of nonradioactive SR-49 059. In conclusion, our study shows that [H-3]SR-49059 is a suitable probe to investigate V-1a receptors in the rat brain. We also demonstrate that al though this compound is not able to enter the brain tissue from the periphe ral circulation, it does bind specifically to regions devoid of blood-brain barrier and known to be involved in autonomic regulations.