Characterization of a Novel, Linear Radioiodinated Vasopressin Antagonist: An Excellent Radioligand for Vasopressin V _1a Receptors

Abstract

We report on the pharmacological properties of a potent and selective linear vasopressin (AVP) V<sub>1a</sub> receptor antagonist HO-Phenylacetyl1-D-Tyr(Me)2-Phe3-Gln4-Asn5-Arg6-Pro7-Arg8-NH<sub>2</sub> (HO-LVA). Iodinated on the phenolic substituent at position 1, [125I]-HO-LVA displayed the highest affinity for rat liver V<sub>1a</sub> receptors (8 pM) ever reported. Furthermore, affinities of HO-LVA and I-HO-LVA for V<sub>1b</sub>, V<sub>2</sub> and oxytocin (OT) receptors was 400- to 1,000-fold lower than for V<sub>1a</sub> receptors, rendering it a highly selective ligand. Both HO-LVA and its iodinated derivative are V<sub>1a</sub> antagonists, they potently inhibited AVP-induced inositol-phosphate accumulation in WRK<sub>1</sub> cells, and also, although with a much lower potency, the AVP-induced ACTH release from freshly prepared pituitary cells. Using autoradiography [125I]-HO-LVA appeared to be the first radioligand to successfully identify and localize the presence of V<sub>1a</sub> receptors in rat liver and blood vessel walls. Moreover, several new brain regions expressing V<sub>1a</sub> receptors could be identified, in addition to those brain regions that were previously identified with other radiolabelled AVP analogues.