Synthesis and evaluation of radioiodinated 1-(2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl)piperidin-4-amine derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging

Nurmaya Effendi, Kazuma Ogawa, Kenji Mishiro, Takeshi Takarada, Daisuke Yamada, Yoji Kitamura, Kazuhiro Shiba, Takehiko Maeda, Akira Odani

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor and it is upregulated in various malignant tumors. Radiolabeled PDGFRβ inhibitors can be a convenient tool for the imaging of tumors overexpressing PDGFRβ. In this study, [125I]-1-(5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl)piperidin-4-amine ([125I]IIQP) and [125I]-N-3-iodobenzoyl-1-(2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl)-piperidin-4-amine ([125I]IB-IQP) were designed and synthesized, and their potential as PDGFRβ imaging agents was evaluated. In cellular uptake experiments, [125I]IIQP and [125I]IB-IQP showed higher uptake by PDGFRβ-positive cells than by PDGFRβ-negative cells, and the uptake in PDGFRβ-positive cells was inhibited by co-culture with PDGFRβ ligands. The biodistribution of both radiotracers in normal mice exhibited hepatobiliary excretion as the main route. In mice inoculated with BxPC3-luc (PDGFRβ-positive), the tumor uptake of radioactivity at 1h after the injection of [125I]IIQP was significantly higher than that after the injection of [125I]IB-IQP. These results indicated that [125I]IIQP can be a suitable PDGFRβ imaging agent. However, further modification of its structure will be required to obtain a more appropriate PDGFRβ-targeted imaging agent with a higher signal/noise ratio.

Original languageEnglish
JournalBioorganic and Medicinal Chemistry
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Platelet-Derived Growth Factor Receptors
Amines
Derivatives
Imaging techniques
Tumors
Cells
Neoplasms
Injections
Radioactivity
Receptor Protein-Tyrosine Kinases
Coculture Techniques
Cell culture

Keywords

  • Molecular imaging
  • PDGFRβ
  • Radiotracer
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

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

Cite this

@article{21d51e65e1dc451f9cf80b74bf4f7267,
title = "Synthesis and evaluation of radioiodinated 1-(2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl)piperidin-4-amine derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging",
abstract = "Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor and it is upregulated in various malignant tumors. Radiolabeled PDGFRβ inhibitors can be a convenient tool for the imaging of tumors overexpressing PDGFRβ. In this study, [125I]-1-(5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl)piperidin-4-amine ([125I]IIQP) and [125I]-N-3-iodobenzoyl-1-(2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl)-piperidin-4-amine ([125I]IB-IQP) were designed and synthesized, and their potential as PDGFRβ imaging agents was evaluated. In cellular uptake experiments, [125I]IIQP and [125I]IB-IQP showed higher uptake by PDGFRβ-positive cells than by PDGFRβ-negative cells, and the uptake in PDGFRβ-positive cells was inhibited by co-culture with PDGFRβ ligands. The biodistribution of both radiotracers in normal mice exhibited hepatobiliary excretion as the main route. In mice inoculated with BxPC3-luc (PDGFRβ-positive), the tumor uptake of radioactivity at 1h after the injection of [125I]IIQP was significantly higher than that after the injection of [125I]IB-IQP. These results indicated that [125I]IIQP can be a suitable PDGFRβ imaging agent. However, further modification of its structure will be required to obtain a more appropriate PDGFRβ-targeted imaging agent with a higher signal/noise ratio.",
keywords = "Molecular imaging, PDGFRβ, Radiotracer, Tyrosine kinase inhibitor",
author = "Nurmaya Effendi and Kazuma Ogawa and Kenji Mishiro and Takeshi Takarada and Daisuke Yamada and Yoji Kitamura and Kazuhiro Shiba and Takehiko Maeda and Akira Odani",
year = "2017",
doi = "10.1016/j.bmc.2017.08.025",
language = "English",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Synthesis and evaluation of radioiodinated 1-(2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl)piperidin-4-amine derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging

AU - Effendi, Nurmaya

AU - Ogawa, Kazuma

AU - Mishiro, Kenji

AU - Takarada, Takeshi

AU - Yamada, Daisuke

AU - Kitamura, Yoji

AU - Shiba, Kazuhiro

AU - Maeda, Takehiko

AU - Odani, Akira

PY - 2017

Y1 - 2017

N2 - Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor and it is upregulated in various malignant tumors. Radiolabeled PDGFRβ inhibitors can be a convenient tool for the imaging of tumors overexpressing PDGFRβ. In this study, [125I]-1-(5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl)piperidin-4-amine ([125I]IIQP) and [125I]-N-3-iodobenzoyl-1-(2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl)-piperidin-4-amine ([125I]IB-IQP) were designed and synthesized, and their potential as PDGFRβ imaging agents was evaluated. In cellular uptake experiments, [125I]IIQP and [125I]IB-IQP showed higher uptake by PDGFRβ-positive cells than by PDGFRβ-negative cells, and the uptake in PDGFRβ-positive cells was inhibited by co-culture with PDGFRβ ligands. The biodistribution of both radiotracers in normal mice exhibited hepatobiliary excretion as the main route. In mice inoculated with BxPC3-luc (PDGFRβ-positive), the tumor uptake of radioactivity at 1h after the injection of [125I]IIQP was significantly higher than that after the injection of [125I]IB-IQP. These results indicated that [125I]IIQP can be a suitable PDGFRβ imaging agent. However, further modification of its structure will be required to obtain a more appropriate PDGFRβ-targeted imaging agent with a higher signal/noise ratio.

AB - Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor and it is upregulated in various malignant tumors. Radiolabeled PDGFRβ inhibitors can be a convenient tool for the imaging of tumors overexpressing PDGFRβ. In this study, [125I]-1-(5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl)piperidin-4-amine ([125I]IIQP) and [125I]-N-3-iodobenzoyl-1-(2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl)-piperidin-4-amine ([125I]IB-IQP) were designed and synthesized, and their potential as PDGFRβ imaging agents was evaluated. In cellular uptake experiments, [125I]IIQP and [125I]IB-IQP showed higher uptake by PDGFRβ-positive cells than by PDGFRβ-negative cells, and the uptake in PDGFRβ-positive cells was inhibited by co-culture with PDGFRβ ligands. The biodistribution of both radiotracers in normal mice exhibited hepatobiliary excretion as the main route. In mice inoculated with BxPC3-luc (PDGFRβ-positive), the tumor uptake of radioactivity at 1h after the injection of [125I]IIQP was significantly higher than that after the injection of [125I]IB-IQP. These results indicated that [125I]IIQP can be a suitable PDGFRβ imaging agent. However, further modification of its structure will be required to obtain a more appropriate PDGFRβ-targeted imaging agent with a higher signal/noise ratio.

KW - Molecular imaging

KW - PDGFRβ

KW - Radiotracer

KW - Tyrosine kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85027998133&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027998133&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2017.08.025

DO - 10.1016/j.bmc.2017.08.025

M3 - Article

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

ER -