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 18F-labeled cyclooxygenase (COX) inhibitors. 18F-SC63217 is selective to COX-1 and has a COX-1 inhibitory concentration of 50% (IC(50)) < 10 nmol/L and a COX-2 IC(50) > 100 micromol/L. 18F-SC58125 has IC(50) values of >100 micromol/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-gamma. 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.


CONCLUSIONS
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.
McCarthy
Timothy J
TJ
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Sheriff
Ahmed U
AU
Graneto
Matthew J
MJ
Talley
John J
JJ
Welch
Michael J
MJ
D000818:Animals; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis; D005260:Female; D005462:Fluorine Radioisotopes; D066298:In Vitro Techniques; D007553:Isotope Labeling; D051379:Mice; D010215:Papio; D011720:Pyrazoles / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D016861:Cyclooxygenase Inhibitors; D005462:Fluorine Radioisotopes; D011720:Pyrazoles; C447499:SC 63217; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole