Jeff Reese
Last active: 1/7/2021

Fluorinated COX-2 inhibitors as agents in PET imaging of inflammation and cancer.

Uddin MJ, Crews BC, Ghebreselasie K, Huda I, Kingsley PJ, Ansari MS, Tantawy MN, Reese J, Marnett LJ
Cancer Prev Res (Phila). 2011 4 (10): 1536-45

PMID: 21900596 · PMCID: PMC3214660 · DOI:10.1158/1940-6207.CAPR-11-0120

COX-2 is a major contributor to the inflammatory response and cancer progression so it is an important target for prevention and therapy. COX-2 is absent or expressed at low levels in most epithelial cells but is found at high levels in inflammatory lesions, and many premalignant and malignant tumors. Thus, it is an attractive target for molecular imaging. We report a series of novel fluorinated imaging agents, derived from indomethacin or celecoxib that selectively inhibit COX-2. The most promising lead, compound 7, was a fluorinated derivative of celecoxib. Kinetic analysis revealed that this fluorinated compound is a slow, tight-binding inhibitor of COX-2 and exhibits minimal inhibitory activity against COX-1. Efficient incorporation of (18)F into compound 7 by radiochemical synthesis and intravenous injection provided sufficient signal for in vivo positron emission tomography (PET) imaging. Selective uptake of (18)F-7 was observed in inflamed rat paws compared with the noninflamed contralateral paws and uptake was blocked by pretreatment with the COX-2 inhibitor, celecoxib. Uptake of (18)F-7 was not observed when inflammation was induced in COX-2-null mice. In nude mice bearing both a COX-2-expressing human tumor xenograft (1483) and a COX-2-negative xenograft (HCT116), (18)F-7 selectively accumulated in the COX-2-expressing tumor. Accumulation was blocked by pretreatment of the animals with celecoxib. The in vitro and in vivo properties of compound 7 suggest it will be a useful probe for early detection of cancer and for evaluation of the COX-2 status of premalignant and malignant tumors.

MeSH Terms (20)

Animals Celecoxib Cyclooxygenase 2 Inhibitors Female Halogenation Humans Indomethacin Inflammation Male Mice Mice, Nude Molecular Imaging Neoplasms Positron-Emission Tomography Pyrazoles Radiopharmaceuticals Rats Rats, Sprague-Dawley Sulfonamides Tumor Cells, Cultured

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