Evaluation of [(11)C]rofecoxib as PET tracer for cyclooxygenase 2 overexpression in rat models of inflammation.

BACKGROUND

Overexpression of cyclooxygenase type 2 (COX-2) is triggered by inflammatory stimuli, but it also plays a prominent role in the initiation and progression of various diseases. This study aims to investigate [(11)C]rofecoxib as a positron emission tomography (PET) tracer for COX-2 expression.

METHODS

[(11)C]Rofecoxib was prepared by methylation of its sulphinate precursor. Regional brain distribution and specific binding of [(11)C]rofecoxib in healthy rats was studied by ex vivo biodistribution and autoradiography. Regional brain distribution and PET imaging studies were also performed on rats with severe encephalitis, caused by nasal infection with herpes simplex virus (HSV). Finally, ex vivo biodistribution and blocking studies were carried in rats with a sterile inflammation, induced by intramuscular turpentine injection.

RESULTS

[(11)C]rofecoxib brain uptake in control animals corresponded with the known distribution of COX-2. Pretreatment with NS398 significantly reduced tracer uptake in the cingulate/frontopolar cortex, whereas the reduction in hippocampus approached significance. Ex vivo autoradiography also revealed preferential tracer uptake in hippocampus and cortical areas that could be blocked by NS398. In HSV-infected animals, [(11)C]rofecoxib uptake was moderately increased in all brain regions, but it could not be blocked with indomethacin. Yet, some PET images revealed increased tracer uptake in brain areas with microglia activation. In turpentine-injected animals, [(11)C]rofecoxib uptake in inflamed muscle was not higher than in control muscle and could not be blocked with NS398. Indomethacin caused a slight reduction in muscle uptake.

CONCLUSIONS

Despite the apparent correlation between [(11)C]rofecoxib uptake and COX-2 distribution in healthy rats, [(11)C]rofecoxib could not unambiguously detect COX-2 overexpression in two rat models of inflammation.