Radioiodinated endothelin-1: A radiotracer for imaging endothelin receptordistribution and occupancy

Endothelin (ET) is one of the most potent vasoconstrictors known. Recently, ET has been implicated in various diseases, e.g., acute renal failure and congestive heart failure, which present the possibility of treating such di seases with endothelin receptor antagonists. However, establishing the dosa ges for these antagonists may be difficult because no convenient physiologi c indicator of action exists, and because of complexities in receptor funct ion. Two receptor subtypes have been identified for which selective antagon ists have been reported (e.g., BQ-123 for the ETA receptor and BQ-788 for t he ETB receptor). Of the three natural peptide hormones (ET-1, ET-2, and ET -3), ET-1 exhibits high affinity for both subtypes of receptor. Using the s elective peptide antagonists, and a nonpeptide antagonist with relatively b alanced affinity for the two subtypes (L-749,329), we have characterized th e interactions of [I-125]ET-1 with its receptors in vivo (in rat). BQ-123, BQ-788, and L-749,329 inhibited binding consistent with binding to a single receptor site. However, the sum of inhibition by the selective antagonist was greater than 100% las defined by inhibition with L-749,329), which sugg ests (a) lower in vivo selectivity than determined in vitro and/or (b) rece ptor subtype interactions. The latter explanation is supported, in part, by in vitro autoradiographic studies as well as studies in isolated tissues a nd cells. We synthesized ET-1 labeled with I-123 and obtained images of rec eptor distribution in both rat and rhesus monkey and have demonstrated our ability to visualize, via planar, noninvasive imaging, the occupancy of end othelin receptor by antagonists in both kidney and lung. [I-123]ET-1 can th erefore be used to determine clinical dosages of antagonist needed for rece ptor saturation. NUCL MED BIOL 26;2:193-199, 1999. (C) 1999 Elsevier Scienc e Inc. All rights reserved.