Radiosynthesis of a ¹⁸F-labeled 2,3-diarylsubstituted indole via McMurry coupling for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo

The radiosynthesis of 3-(4-[¹⁸F]fluorophenyl)-2-(4-methylsulfonylphenyl)-1H-indole [¹⁸F]3 as PET radiotracer for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo is described. [¹⁸F]3 was prepared by McMurry cyclization of a ¹⁸F-labeled intermediate with low valent titanium and zinc via a two-step procedure in a remote controlled synthesizer unit including HPLC purification and solid phase extraction. In this way [¹⁸F]3 was synthesized in 80 min synthesis time in 10% total decay corrected yield from [¹⁸F]fluoride in radiochemical purity >98% and a specific activity of 74-91 GBq/µmol. [¹⁸F]3 was evaluated in vitro using pro-inflammatory stimulated THP-1 and COX-2 expressing tumor cell lines (FaDu, A2058, HT-29), where the radiotracer uptake was shown to be consistent with up regulated COX-2 expression. The stability of [¹⁸F]3 was determined by incubation in rat whole blood and plasma in vitro and by metabolite analysis of arterial blood samples in vivo, showing with 75% of original compound after 60 min an acceptable high metabolic stability. In vivo kinetics and tumor uptake were investigated by dynamic small animal PET studies on HT-29 tumor-bearing mice, and revealed in contrast to the in vitro results no substantial tumor accumulation of [¹⁸F]3. These data indicate that the radiotracer is not suitable for functional imaging of COX-2 in rodent models in vivo. However it should be noted that McMurry cyclization in PET chemistry gives access to 18F-labeled diaryl-substituted heterocyles that hold promise as new radiolabeled COX-2 inhibitors.