Synthesis and in Vitro Characterization of Radioiodinatable Benzodiazepines Selective for Type 1 and Type 2 Cholecystokinin Receptors

Radiolabeled antagonists of specific peptide receptors identify a higher number of receptor binding sites than agonists and may thus be preferable for in vivo tumor targeting. In this study, two novel radioiodinated 1,4-benzodiazepines, (S)-1-(3-iodophenyl)-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin3-yl)urea (9) and (R)-1-(3-iodophenyl)-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e][1,4]diazepin-3-yl)urea (7), were developed. They were characterized in vitro as high affinity selective antagonists at cholecystokinin types 1 and 2 (CCK1 and CCK2) receptors using receptor binding, calcium mobilization, and internalization studies. Their binding to human tumor tissues was assessed with in vitro receptor autoradiography and compared with an established peptidic CCK agonist radioligand. The I-125-labeled CCK1 receptor-selective compound 9 often revealed a substantially higher amount of CCK1 receptor binding sites in tumors than the agonist I-125-CCK. Conversely, the radioiodinated CCK2 receptor-selective compound 7 showed generally weaker tumor binding than I-125-CCK. In conclusion, compound 9 is an excellent radioiodinated nonpeptidic antagonist ligand for direct and selective labeling of CCK1 receptors in vitro. Moreover, it represents a suitable candidate to test antagonist binding to CCK1 receptor-expressing tumors in vivo.