Synthesis and evaluation of ortho-[ ¹⁸F] fluorocelecoxib for COX-2 cholangiocarcinoma imaging

Abstract

Background

An ¹⁸F-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-[ ¹⁸F]fluorocelecoxib using positron emission tomography (PET). The binding affinity of ortho-[ ¹⁸F]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-[ ¹⁸F]fluorocelecoxib than that by usual CCA cells from 10 to 60 minutes post incubation. Competitive inhibition (blocking) of the tracer uptake of ortho-[ ¹⁸F]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-[ ¹⁸F]fluorocelecoxib through the tail vein. Study of ortho-[ ¹⁸F]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.