Characterization of a Novel, Linear Radioiodinated Vasopressin Antagonist: An Excellent Radioligand for Vasopressin V1a Receptors

Abstract

We report on the pharmacological properties of a potent and selective linear vasopressin (AVP) V_1a receptor antagonist HO-Phenylacetyl¹-D-Tyr(Me)²-Phe³-Gln⁴-Asn⁵-Arg⁶-Pro⁷-Arg⁸-NH₂ (HO-LVA). Iodinated on the phenolic substituent at position 1, [¹²⁵I]-HO-LVA displayed the highest affinity for rat liver V_1a receptors (8 pM) ever reported. Furthermore, affinities of HO-LVA and I-HO-LVA for V_1b, V₂ and oxytocin (OT) receptors was 400- to 1,000-fold lower than for V_1a receptors, rendering it a highly selective ligand. Both HO-LVA and its iodinated derivative are V_1a antagonists, they potently inhibited AVP-induced inositol-phosphate accumulation in WRK₁ 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_1a receptors in rat liver and blood vessel walls. Moreover, several new brain regions expressing V_1a receptors could be identified, in addition to those brain regions that were previously identified with other radiolabelled AVP analogues.