A benzenesulfonamide derivative as a novel PET radioligand for CXCR4. Issue 2 (15th January 2020)

• Record Type: Journal Article
• Authors: Oum, Yoon Hyeun; Shetty, Dinesh; Yoon, Younghyoun; Liang, Zhongxing; Voll, Ronald J.; Goodman, Mark M.; Shim, Hyunsuk
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 2(2020)
• Publication Date: 2020-01-15
• Subjects: C-X-C chemokine receptor type 4 (CXCR4) -- CXCL12 -- Molecular imaging probe -- Positron emission tomography (PET) -- Inflammation -- Head and neck cancer -- Metastasis; GPCRs G-protein-coupled receptors -- CXCR4 C-X-C chemokine receptor type 4 -- CXCL12 C-X-C chemokine ligand 12 -- SDF-1 stromal cell-derived factor-1 -- HIV human immunodeficiency virus -- SCCHN squamous cell carcinoma of head and neck -- PDB protein databank -- EC effective concentration -- DTPA diethylenetriamine pentaacetate -- DOTA dodecane tetraacetic acid -- NOTA triazacyclononane triacetic acid; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115240
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A novel small molecular CXCR4-targeted PET tracer without chelating moiety is designed based on benzenesulfonamide scaffold via chemoinformatic and molecular modeling approach. In vitro binding assay and chemotaxis inhibition assay affirm the affinity and functional activity of the novel agent with CXCR4. The novel CXCR4-targeted F-18 PET agent demonstrates the ability to visualize acute inflammation, head and neck cancer, and cancer lung metastasis in mouse models. 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 ([ 18 F]5 ) demonstrates a competitive cellular uptake against CXCL12 in a dose-dependent manner. Further, microPET images of [ 18 F]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.