A benzenesulfonamide derivative as a novel PET radioligand for CXCR4

• Type of Material: Article
• Authors: Yoon Hyeun Oum, Emory University; Dinesh Shetty, Emory University; Younghyoun Yoon, Emory University; Zhongxing Liang, Emory University; Ronald Voll, Emory University; Mark Goodman, Emory University; Hyunsuk Shim, Emory University
• Language: English
• Date: 2020-01-15
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2019
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmc.2019.115240
• Title of Journal or Parent Work: BIOORGANIC & MEDICINAL CHEMISTRY
• Volume: 28
• Issue: 2
• Start Page: 115240
• End Page: 115240
• Keywords: Pharmacology & Pharmacy; Life Sciences & Biomedicine; CXCL12; HUMAN CANCER XENOGRAFTS; Physical Sciences; Metastasis; GROWTH; C-X-C chemokine receptor type 4 (CXCR4); Head and neck cancer; SYSTEM; TRACER; Chemistry; IMAGING AGENTS; Chemistry, Organic; SUBSETS; Positron emission tomography (PET); Inflammation; LIGAND; EXPRESSION; Molecular imaging probe; CHEMOKINE RECEPTOR CXCR4; SMALL-MOLECULE; Science & Technology; Chemistry, Medicinal; Biochemistry & Molecular Biology
• Research Categories: Biology, Molecular; Chemistry, Biochemistry; Chemistry, Organic

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.