Design, Synthesis, and Evaluation of an 18F-Labeled Radiotracer Based on Celecoxib-NBD for Positron Emission Tomography (PET) Imaging of Cyclooxygenase-2 (COX-2)

Article abstract of DOI:10.1002/cmdc.201500287

A series of novel fluorine-containing cyclooxygenase-2 (COX-2) inhibitors was designed and synthesized based on the previously reported fluorescent COX-2 imaging agent celecoxib-NBD (3; NBD=7-nitrobenzofurazan). In vitro COX-1/COX-2 inhibitory data show that N-(4-fluorobenzyl)-4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide (5; IC₅₀=0.36 μM, SI>277) and N-fluoromethyl-4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide (6; IC₅₀=0.24 μM, SI>416) are potent and selective COX-2 inhibitors. Compound 5 was selected for radiolabeling with the short-lived positron emitter fluorine-18 (¹⁸F) and evaluated as a positron emission tomography (PET) imaging agent. Radiotracer [¹⁸F]5 was analyzed in vitro and in vivo using human colorectal cancer model HCA-7. Although radiotracer uptake into COX-2-expressing HCA-7 cells was high, no evidence for COX-2-specific binding was found. Radiotracer uptake into HCA-7 tumors in vivo was low and similar to that of muscle, used as reference tissue. From fluorescence to PET imaging: In line with the success of our fluorescent COX-2 imaging celecoxib-NBD probe, we extend our efforts to prepare an ¹⁸F-labeled PET imaging probe for in vivo detection of COX-2 expression in colorectal cancer. Herein we report the preparation of a series of COX-2 inhibitors, the radiosynthesis of an ¹⁸F-labeled radiotracer, results of in vitro cell uptake studies in colorectal cancer HCA-7 cells, radiometabolite analysis, and in vivo PET imaging studies in HCA-7 tumor-bearing NIH-III mice.