Synthesis and in vitro characterization of radioiodinatable benzodiazepines selective for type 1 and Type 2 cholecystokinin receptors

Eyup Akgun, Meike Körner, Fan Gao, Kaleeckal G. Harikumar, Beatrice Waser, Jean Claude Reubi, Philip S Portoghese, Laurence J. Miller

Research output: Contribution to journalArticle

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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 radioiodinated1,4- 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 125I-labeled CCK 1 receptor-selective compound 9 often revealed a substantially higher amount of CCK 1 receptor binding sites in tumors than the agonist 125I-CCK. Conversely, the radioiodinated CCK 2 receptor-selective compound 7 showed generally weaker tumor binding than 125I-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.

Original languageEnglish (US)
Pages (from-to)2138-2147
Number of pages10
JournalJournal of Medicinal Chemistry
Volume52
Issue number7
DOIs
StatePublished - Apr 9 2009

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Cholecystokinin A Receptor
Cholecystokinin B Receptor
Benzodiazepines
Neoplasms
Binding Sites
Cholecystokinin Receptors
Calcium-Sensing Receptors
Peptide Receptors
Cholecystokinin
Autoradiography
In Vitro Techniques
Ligands

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Synthesis and in vitro characterization of radioiodinatable benzodiazepines selective for type 1 and Type 2 cholecystokinin receptors. / Akgun, Eyup; Körner, Meike; Gao, Fan; Harikumar, Kaleeckal G.; Waser, Beatrice; Reubi, Jean Claude; Portoghese, Philip S; Miller, Laurence J.

In: Journal of Medicinal Chemistry, Vol. 52, No. 7, 09.04.2009, p. 2138-2147.

Research output: Contribution to journalArticle

Akgun, Eyup ; Körner, Meike ; Gao, Fan ; Harikumar, Kaleeckal G. ; Waser, Beatrice ; Reubi, Jean Claude ; Portoghese, Philip S ; Miller, Laurence J. / Synthesis and in vitro characterization of radioiodinatable benzodiazepines selective for type 1 and Type 2 cholecystokinin receptors. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 7. pp. 2138-2147.
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