title: Synthesis and in vitro characterization of radioiodinatable benzodiazepines selective for type 1 and type 2 cholecystokinin receptors.
abstract: 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]diazepin-3-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 (CCK(1) and CCK(2)) 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 (125)I-labeled CCK(1) receptor-selective compound 9 often revealed a substantially higher amount of CCK(1) receptor binding sites in tumors than the agonist (125)I-CCK. Conversely, the radioiodinated CCK(2) receptor-selective compound 7 showed generally weaker tumor binding than (125)I-CCK. In conclusion, compound 9 is an excellent radioiodinated nonpeptidic antagonist ligand for direct and selective labeling of CCK(1) receptors in vitro. Moreover, it represents a suitable candidate to test antagonist binding to CCK(1) receptor-expressing tumors in vivo.
authors.affiliation: Department of Molecular Pharmacology, Mayo Clinic, Scottsdale, Arizona 85259, USA.
authors.forename: Eyup
authors.initials: E
authors.lastname: Akgün
authors.forename: Meike
authors.initials: M
authors.lastname: Körner
authors.forename: Fan
authors.initials: F
authors.lastname: Gao
authors.forename: Kaleeckal G
authors.initials: KG
authors.lastname: Harikumar
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Philip S
authors.initials: PS
authors.lastname: Portoghese
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Miller
mesh_terms: D000818:Animals; D001345:Autoradiography; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005704:Gallbladder / Q000000981:diagnostic imaging / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D007889:Leiomyoma / Q000000981:diagnostic imaging / Q000378:metabolism; D008024:Ligands; D008579:Meningioma / Q000000981:diagnostic imaging / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism
chemical_list: C540189:1-(3-iodophenyl)-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)urea; D007457:Iodine Radioisotopes; D008024:Ligands; D010671:Phenylurea Compounds; D019275:Radiopharmaceuticals; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D001569:Benzodiazepines; D002118:Calcium