Design, synthesis, and biological evaluation of radioiodinated benzo[d]imidazole-quinoline derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging

Nurmaya Effendi, Kenji Mishiro, Takeshi Takarada, Daisuke Yamada, Ryuichi Nishii, Kazuhiro Shiba, Seigo Kinuya, Akira Odani, Kazuma Ogawa

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Several malignant tumors and fibrotic diseases are associated with PDGFRβ overexpression and excessive signaling, making this receptor attractive for molecular targeting and imaging approaches. A series of benzo[d]imidazole-quinoline derivatives were designed and synthesized to develop radioiodinated compounds as PDGFRβ-specific imaging probes. The structure activity relationship (SAR) evaluation of the designed compounds was performed. Among them, 2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (5a) and 4-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (5d) exhibited a relatively high PDGFRβ-TK inhibitory potency, whereas iodinated 5a derivative 5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (8) exhibited a superior inhibitory potency as PDGFRβ inhibitor than iodinated 5d derivative 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (11). Furthermore, [ 125 I]8 and [ 125 I]11 were synthesized and evaluated for PDGFRβ radioligand ability, both in vitro and in vivo. Cellular uptake experiments showed that [ 125 I]8 had a higher uptake in BxPC3-luc cells as PDGFRβ-positive cells than [ 125 I]11. Incubation of [ 125 I]8 after pretreatment of PDGFRβ ligands significantly reduced the uptake of [ 125 I]8. In biodistribution experiments using tumor-bearing mice, [ 125 I]8 accumulation in the tumor 1 h postinjection was higher than that of the benzo[d]imidazol-quinoline derivative [ 125 I]IIQP, used in our previous research. These results indicate that [ 125 I]8 could be a promising PDGFRβ imaging agent. Although its clinical application requires further structural modifications, the results obtained in this research may be useful for the development of PDGFRβ-specific radioligands.

Original languageEnglish
Pages (from-to)383-393
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number2
DOIs
Publication statusPublished - Jan 15 2019

Keywords

  • Molecular imaging
  • PDGFRβ
  • Radioligand
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Design, synthesis, and biological evaluation of radioiodinated benzo[d]imidazole-quinoline derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging'. Together they form a unique fingerprint.

Cite this