Radiosynthesis, In Vitro Validation, and In Vivo Evaluation of 18F-Labeled COX-1 and COX-2 Inhibitors

Journal of Nuclear Medicine

Matthew J. Graneto¹  Ahmed U. Sheriff¹  John J. Talley¹  Timothy J. McCarthy¹  Michael J. Welch¹ 

关键词: cyclooxygenase;    PET;    ¹⁸F;    enzyme inhibitors;    SC58125;    SC63217;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

In this article, we describe the radiosynthesis and evaluation of 18F-labeled cyclooxygenase (COX) inhibitors. 18F-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 μmol/L. 18F-SC58125 has IC50 values of >100 μmol/L (COX-1) and <86 nmol/L (COX-2). Methods: SC63217 and SC58125 were both labeled with 18F 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-γ. Both radiotracers were further investigated in vivo using rat biodistribution techniques. Brain uptake of the COX-2 inhibitor, 18F-SC58125, was further investigated by brain PET of a baboon. Results: The in vitro studies showed that uptake of 18F-SC58125 was increased in stimulated cells and was totally inhibited by the addition of nonradioactive SC58125. In contrast, no increase in uptake was seen for 18F-SC63217. In the biodistribution experiments, 18F-SC63217 showed much higher uptake in the small intestine (an organ known to express high levels of COX-1) than did 18F-SC58125. Higher levels of 18F-SC58125 were observed in the kidney, an organ known to contain high levels of COX-2 rather than COX-1. 18F-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 18F-labeled selective inhibitors of COX-1 or COX-2. Both compounds have been fully characterized in vitro and in vivo. Our results indicate that 18F-SC58125 has potential as a marker of COX-2 activity but that, because of high nonspecific binding, 18F-SC63217 was not a good choice as a marker of COX-1.

【 授权许可】

Unknown