Synthesis of 18F-labelled cyclooxygenase-2 (COX-2) inhibitor as a potential PET imaging agent

Abstract

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Objectives: Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandin H2, is expressed in normal brain and kidney, activated macrophages, synoviocytes during inflammation, and malignant epithelial cells. Increasing evidence also suggests a role of COX-2 in the initiation and progression of cancer and a neurotoxic role of COX-2 in neurodegenerative. In vivo imaging of COX-2 would also provide a valuable tool to gain more insight in pathophysiology of diseases involving COX-2. In this study. In this study, we will focus on an COX-2 inhibitor, 6-ethoxy-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (EMFP), it exhibit excellent potency (IC50 = 0.10 µM) and selectivity (SI = 2880). This inhibitor has the structure which permits incorporation of 18F through a simple nucleophilic reaction between [18F]fluorine and triflate precursor. Thus, the goal of this study was to synthesize [18F]EFMP, an 18F-labelled COX-2 inhibitor that could be used for PET studies of COX-2 in vivo.

Methods: Methods: The reference compound and their corresponding trimethylammonium-precursor and bromo-precursor were synthesized via multi-step synthetic approaches. The radiosyntheses of [18F]EFMP was performed in a one step reaction, it was produced by nucleophlic displacement of trimethylammonium-precursor with [18F]fluoride. After ending reaction, the reaction mixture is purified by Sep-Pak C-18 column and HPLC, the desired product was collected for further study.

Results: After rapid Sep-Pak (C-18) purification, the radiolabeled product was purified by HPLC with radiochemical yields ranging10-18% (decay corrected) and total synthesis time of 60-70 min (EOB). The radiochemical purity of [18F]EFMP was verified by analytical HPLC. Co-elution of the radioactive peak with the UV peak of the unlabeled standard confirmed the identity. The specific activity was determined to be 2130±170 Ci/mmol at EOS.

Conclusions: In summary, a successful synthesis of a potential 18F labeled radiotracer for studying COX-2 expression, [18F]EFMP, has been developed via a corresponding trimethylammonium-precursor and is superior to that via bromo-precursor. Radiolabelling can be accomplished in short time, the radiotracer was obtained with high specific activity and radiochemical and chemical purity.

Research Support (if any): This work is supoorted in part by BRTT and NIH R24