A benzenesulfonamide derivative as a novel PET radioligand for CXCR4

Yoon Hyeun Oum; Dinesh Shetty; Younghyoun Yoon; Zhongxing Liang; Ronald J. Voll; Mark M. Goodman; Hyunsuk Shim

doi:10.1016/j.bmc.2019.115240

A benzenesulfonamide derivative as a novel PET radioligand for CXCR4

Yoon Hyeun Oum
, Dinesh Shetty
, Younghyoun Yoon
, Zhongxing Liang
, Ronald J. Voll
, Mark M. Goodman
, Hyunsuk Shim

Chemistry

Emory University School of Medicine
Emory University

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

CXCR4 is involved in various diseases such as inflammation, tumor growth, and cancer metastasis through the interaction with its natural endogenous ligand, chemokine CXCL12. In an effort to develop imaging probes for CXCR4, we developed a novel small molecule CXCR4-targeted PET agent (compound 5) by combining our established benzenesulfonamide scaffold with a labeling component by virtue of click chemistry. 5 shows nanomolar affinity (IC₅₀ = 6.9 nM) against a known CXCR4 antagonist (TN14003) and inhibits more than 65% chemotaxis at 10 nM in vitro assays. Radiofluorinated compound 5 ([¹⁸F]5) demonstrates a competitive cellular uptake against CXCL12 in a dose-dependent manner. Further, microPET images of [¹⁸F]5 exhibits preferential accumulation of radioactivity in the lesions of λ-carrageenan-induced paw edema, human head and neck cancer orthotopic xenograft, and metastatic lung cancer of each mouse model.

Original language	British English
Article number	115240
Journal	Bioorganic and Medicinal Chemistry
Volume	28
Issue number	2
DOIs	https://doi.org/10.1016/j.bmc.2019.115240
State	Published - 15 Jan 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

C-X-C chemokine receptor type 4 (CXCR4)
CXCL12
Head and neck cancer
Inflammation
Metastasis
Molecular imaging probe
Positron emission tomography (PET)

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title = "A benzenesulfonamide derivative as a novel PET radioligand for CXCR4",

abstract = "CXCR4 is involved in various diseases such as inflammation, tumor growth, and cancer metastasis through the interaction with its natural endogenous ligand, chemokine CXCL12. In an effort to develop imaging probes for CXCR4, we developed a novel small molecule CXCR4-targeted PET agent (compound 5) by combining our established benzenesulfonamide scaffold with a labeling component by virtue of click chemistry. 5 shows nanomolar affinity (IC50 = 6.9 nM) against a known CXCR4 antagonist (TN14003) and inhibits more than 65\% chemotaxis at 10 nM in vitro assays. Radiofluorinated compound 5 ([18F]5) demonstrates a competitive cellular uptake against CXCL12 in a dose-dependent manner. Further, microPET images of [18F]5 exhibits preferential accumulation of radioactivity in the lesions of λ-carrageenan-induced paw edema, human head and neck cancer orthotopic xenograft, and metastatic lung cancer of each mouse model.",

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AU - Oum, Yoon Hyeun

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AU - Voll, Ronald J.

AU - Goodman, Mark M.

AU - Shim, Hyunsuk

N1 - Funding Information: The authors wish to thank Dr. Bryan Cox, Dr. Qi Shi and the late Dr. James P. Snyder for the help with computational modeling. The authors also thank Dr. Dennis C. Liotta for allowing them to use computation facilities. This study was financially supported by a research grant from NIH NCI ( R01 CA165306 ). Appendix A Publisher Copyright: © 2019 Elsevier Ltd

PY - 2020/1/15

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N2 - CXCR4 is involved in various diseases such as inflammation, tumor growth, and cancer metastasis through the interaction with its natural endogenous ligand, chemokine CXCL12. In an effort to develop imaging probes for CXCR4, we developed a novel small molecule CXCR4-targeted PET agent (compound 5) by combining our established benzenesulfonamide scaffold with a labeling component by virtue of click chemistry. 5 shows nanomolar affinity (IC50 = 6.9 nM) against a known CXCR4 antagonist (TN14003) and inhibits more than 65% chemotaxis at 10 nM in vitro assays. Radiofluorinated compound 5 ([18F]5) demonstrates a competitive cellular uptake against CXCL12 in a dose-dependent manner. Further, microPET images of [18F]5 exhibits preferential accumulation of radioactivity in the lesions of λ-carrageenan-induced paw edema, human head and neck cancer orthotopic xenograft, and metastatic lung cancer of each mouse model.

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A benzenesulfonamide derivative as a novel PET radioligand for CXCR4

Abstract

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Keywords

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