Philip Kingsley
Last active: 3/12/2020

Discovery of Furanone-Based Radiopharmaceuticals for Diagnostic Targeting of COX-1 in Ovarian Cancer.

Uddin MJ, Wilson AJ, Crews BC, Malerba P, Uddin MI, Kingsley PJ, Ghebreselasie K, Daniel CK, Nickels ML, Tantawy MN, Jashim E, Manning HC, Khabele D, Marnett LJ
ACS Omega. 2019 4 (5): 9251-9261

PMID: 31172046 · PMCID: PMC6545551 · DOI:10.1021/acsomega.9b01093

In vivo targeting and visualization of cyclooxygenase-1 (COX-1) using multimodal positron emission tomography/computed tomography imaging represents a unique opportunity for early detection and/or therapeutic evaluation of ovarian cancer because overexpression of COX-1 has been characterized as a pathologic hallmark of the initiation and progression of this disease. The furanone core is a common building block of many synthetic and natural products that exhibit a wide range of biological activities. We hypothesize that furanone-based COX-1 inhibitors can be designed as imaging agents for the early detection, delineation of tumor margin, and evaluation of treatment response of ovarian cancer. We report the discovery of 3-(4-fluorophenyl)-5,5-dimethyl-4-(-tolyl)furan-2(5)-one (FDF), a furanone-based novel COX-1-selective inhibitor that exhibits adequate in vivo stability, plasma half-life, and pharmacokinetic properties for use as an imaging agent. We describe a novel synthetic scheme in which a Lewis acid-catalyzed nucleophilic aromatic deiodo[F]fluorination reaction is utilized for the radiosynthesis of [F]FDF. [F]FDF binds efficiently to COX-1 in vivo and enables sensitive detection of ovarian cancer in subcutaneous and peritoneal xenograft models in mice. These results provide the proof of principle for COX-1-targeted imaging of ovarian cancer and identify [F]FDF as a promising lead compound for further preclinical and clinical development.

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