Radiosynthesis, in vitro validation, and in vivo evaluation of 18F-labeled COX-1 and COX-2 inhibitors

In this article, we describe the radiosynthesis and evaluation of F-18-labeled cyclooxygenase (COX) inhibitors. F-18-SC63217 is selective to COX-1 and has a COX-1 inhibitory concentration of 50% (IC50) < 10 nmol/L and a COX-2 IC50 > 100 mumoI/L. F-18-SC58125 has IC50 values of >100 mumoI/L (COX-1) and <86 nmol/L (COX-2). Methods: SC63217 and SC58125 were both labeled with F-18 by nucleophilic displacement of a trimethylammonium triflate salt using a dedicated microwave cavity. Each compound was evaluated in vitro using a murine macrophage cell line (J774). COX-2 was stimulated in these cells by treatment with lipopolysaccharide and interferon-gamma. Both radiotracers were further investigated in vivo using rat biodistribution techniques. Brain uptake of the COX-2 inhibitor, F-18-SC58125, was further investigated by brain PET of a baboon. Results: The in vitro studies showed that uptake of F-18-SC58125 was increased in stimulated cells and was totally inhibited by the addition of non-radioactive SC58125. In contrast, no increase in uptake was seen for F-18-SC63217. In the biodistribution experiments, F-18-SC63217 showed much higher uptake in the small intestine (an organ known to express high levels of COX-1) than did F-18-SC58125. Higher levels of F-18-SC58125 were observed in the kidney, an organ known to contain high levels of COX-2 rather than COX-1. F-18-SC58125 was retained in brain tissue. PET images of the baboon showed no regional distribution of the radiotracer in the brain. Conclusion: We have developed a radiosynthetic route that can yield F-18-labeled selective inhibitors of COX-1 or COX-2. Both compounds have been fully characterized in vitro and in vivo. Our results indicate that F-18-SC58125 has potential as a marker of COX-2 activity but that, because of high nonspecific binding, F-18-SC63217 was not a good choice as a marker of COX-1.