Radiosynthesis andin vivo evaluation of11C-Iabeled 1,5-diarylpyrazole derivatives for mapping cyclooxygenases

Abstract

We prepared 11C-labeled 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole ([11C]1) and 4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide ([11C]2) for imaging COX-1 and COX-2 isoforms, respectively, by positron emission tomography. [11C]1 and [11C]2 were synthesized in high radiochemical yields by O-[11C]methylation with [11C]methyl triflate in acetone containing an equivalent of NaOH as a base with respect to the phenolic precursors. In vivo evaluation in rats bearing AH109A hepatoma demonstrated minimal specific binding of [11C] to COX-1 in peripheral organs, such as the spleen and small intestine. Carrier-saturable uptake of [11C]2 was found in the spleen, but COX-2-specific binding of [11C]2 was not identifiable in the brain, AH109A hepatoma or other peripheral organs, although ex vivo autoradiography showed regionally different distribution in the brain and AH109A. The results suggest that neither [11C]1 nor [11C]2 is a suitable radioligand for in vivo biomarkers of COX enzymes, mainly because of marked non-specific binding.

Radiosynthesis and Evaluation of 11C-Labeled Diaryl-Substituted Imidazole and Indole Derivatives for Mapping Cyclooxygenase-2

“…All three tracers showed low uptake in tumor tissue and no saturable or COX-specific binding, although we previously confirmed that AH109H tumor cells expressed the COX-2 protein. 23) In the brain, high basal levels of COX-2 were found in the neocortex, hippocampus, amygdale, and limbic cortices. 33,34) We did not find COX-specific binding in vivo in the brain for all three tracers by the blocking experiments.…”

“…33,34) We did not find COX-specific binding in vivo in the brain for all three tracers by the blocking experiments. The possibility that unlabeled COX-2 selective inhibitors used in this study, for some unknown reasons, do not have an effect on the in vivo specific bindings of [ 11 19,23) and the lipophilicity of the three tracers was expected to be suitable for crossing the blood-brain barrier (BBB). We hypothesized that the low uptake of [ 11 C]2 and [ 11 C]3 in the brain might be caused by the efflux action of P-gp in the blood-brain barrier (BBB).…”

“…Recently, we also synthesized a positron-emitting 1,5-diarylpyrazole derivative with higher affinity for COX-2 (COX-1, IC 50 ϭ 2.6 mM; COX-2, IC 50 ϭ8 nM), 4-[5-(4-[ 11 C]methoxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide, but it was not suitable for in vivo mapping of the COX-2 isoform because of its high non-specific binding. 23) We thought that these unsuccessful results may be caused by the fact that affinity and selectivity of the target compounds for COX-2 would not be enough in vivo. In this study, we chose three very potent and selective COX-2 inhibitors for 11 C-labeling ( Fig.…”

C-11 Radiochemistry in Cancer Imaging Applications

“…5-(4-chlorophenyl)-1-(4-[ 11 C]methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole, is a selective COX-1 inhibitor (COX-1 IC 50 = 9 nM; COX-2 IC 50 = 6.3 μM) [114], and 4-[5-(4-[ 11 C]methoxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide, is a selective COX-2 inhibitor(COX-1 IC 50 = 2.6 μM; COX-2 IC 50 = 8 nM) (Fig. (22)) [115,116]. When using [ 11 C]methyl iodide for the O-[ 11 C]methylation in NaH/DMF at 120ºC for (Fig.…”

Development of PET radiopharmaceuticals and their clinical applications at the Positron Medical Center

“…at Kyushu University, we prepared four 11 C‐labeled COX inhibitors: one for COX‐1 and three for COX‐2. Unfortunately, none of them might be a good choice as an in vivo radioligand for COX 96,97 . Further studies are underway.…”