Synthesis of an ¹¹C-labelled cyclooxygenase-2 (COX-2) inhibitor and PET imaging in HT-29 and FaDu tumor bearing mice

Cyclooxygenase-2 (COX-2) is an enzyme induced during inflammation by various stimuli, but overexpression of COX-2 has been observed also in oncogenesis in a variety of tumors. Although several COX-2 inhibitors have recently been radiolabeled with isotopes for positron emission tomography (PET), their potential for tumor imaging has not been explored extensively. Herein we report the synthesis and radiopharmacological evaluation of 1-(4-[¹¹C]methoxyphenyl)-2-(4-methylsulfonylphenyl)-1-cyclopentene as novel ¹¹C-labelled radiotracer for PET imaging of COX-2.

Methods:

The radiolabeling was performed via a ¹¹C-methylation reaction of the corresponding desmethyl precursor using [¹¹C]MeI in a TRACERLab FXC module.
Biodistribution studies were performed in normal Wistar rats. Small animal PET studies were performed using xenografted HT-29 and FaDu tumors in mice using a micro-PET^® P4 scanner.

Results:

The radiolabeling was achieved by the reaction of 1-(4-hydroxyphenyl)-2-(4-methylsulfonylphenyl)-1-cyclopentene at 60°C in DMF/aqueous NaOH with [¹¹C]CH₃I. After semi-preparative HPLC purification and solid phase extraction the ¹¹C-labelled COX-2 inhibitor was obtained in 12-14 % decay-corrected radiochemical yield at a specific activity of 30 GBq/µmol at the end-of-synthesis. The radiochemical purity exceeded 97%. Biodistribution in normal rats showed high radioactivity accumulation in the liver, adrenals and brown adipose tissue, reaching 0.6±0.1, 0.7±0.2 and 0.8±0.1 %ID/g after 1 h post injection, respectively. Tumor-to-muscle ratios of 1.7±0.2 and 2.1±0.3, respectively, were determined with small animal PET-studies of xenografted HT-29 and FaDu tumors in mice after 1 h post injection.