Synthesis and evaluation of <em>ortho</em>-[<sup>18</sup>F]fluorocelecoxib for COX-2 cholangiocarcinoma imaging

Abstract

Background: An 18 F-tagged NSAID analog was prepared for use as a probe for COX-2 expression, which is associated with tumor development. Methods: The in vivo uptake of celecoxib was monitored with ortho -[ 18 F]fluorocelecoxib using positron emission tomography (PET). The binding affinity of ortho -[ 18 F]fluorocelecoxib to COX-1 and COX-2 enzymes were assessed using the competitor celecoxib. Results: The IC 50 values were 0.039 μM and 0.024 μM, respectively. A selectivity index of 1.63 was obtained (COX-2 vs COX-1). COX-2 overexpressed cholangiocarcinoma (CCA) murine cells took up more ortho -[ 18 F]fluorocelecoxib than that by usual CCA cells from 10 to 60 minutes post incubation. Competitive inhibition (blocking) of the tracer uptake of ortho -[ 18 F]fluorocelecoxib in the presence of celecoxib by the COX-2 overexpressed CCA cells and the usual CCA cells gave the IC 50 values of 0.5 μM and 46.5 μM, respectively. Based on the in vitro accumulation data and in vivo metabolism half-life (30 min), PET scanning was performed 30–60 min after the administration of ortho -[ 18 F]fluorocelecoxib through the tail vein. Study of ortho -[ 18 F]F-celecoxib in the CCA rats showed a tumor to normal ratio (T/N) of 1.38±0.23 and uptake dose of 1.14±0.25 (%ID/g). Conclusion: The inferior in vivo blocking results of 1.48±0.20 (T/N) and 1.18±0.22 (%ID/g) suggests that the nonspecificity is associated with the complex role of peroxidase or the binding to carbonic anhydrase. Keywords: celecoxib, fluorination, imaging, NSAIDs, blocking, PET