HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McCarthy, T. J. Articles by Welch, M. J. Search for Related Content PubMed PubMed Citation Articles by McCarthy, T. J. Articles by Welch, M. J.

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

¹ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
² Discovery Research, Pharmacia Corporation, St. Louis, Missouri

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-. 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.

Key Words: cyclooxygenase • PET • ¹⁸F • enzyme inhibitors • SC58125 • SC63217

This article has been cited by other articles:

				S. Biswal, D. L. Resnick, J. M. Hoffman, and S. S. Gambhir Molecular Imaging: Integration of Molecular Imaging into the Musculoskeletal Imaging Practice Radiology, September 1, 2007; 244(3): 651 - 671. [Abstract] [Full Text] [PDF]

				E. F.J. de Vries, A. van Waarde, A. R. Buursma, and W. Vaalburg Synthesis and In Vivo Evaluation of 18F-Desbromo-DuP-697 as a PET Tracer for Cyclooxygenase-2 Expression J. Nucl. Med., October 1, 2003; 44(10): 1700 - 1706. [Abstract] [Full Text] [PDF]

				T. F. Massoud and S. S. Gambhir Molecular imaging in living subjects: seeing fundamental biological processes in a new light Genes & Dev., March 1, 2003; 17(5): 545 - 580. [Full Text] [PDF]

				S. M. Lippman and W. K. Hong Cancer Prevention Science and Practice Cancer Res., September 15, 2002; 62(18): 5119 - 5125. [Full Text] [PDF]