Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression

Kuge, Yuji; Katada, Yumiko; Shimonaka, Sayaka; Temma, Takashi; Kimura, Hiroyuki; Kiyono, Yasushi; Yokota, Chiaki; Minematsu, Kazuo; Seki, Koh-ichi; Tamaki, Nagara; Ohkura, Kazue; Saji, Hideo

doi:10.1016/j.nucmedbio.2005.10.004

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 1 , Pages 21-27, January 2006

Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression

Yuji Kuge
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
- Corresponding author. Tel.: +81 75 753 4608; fax: +81 75 753 4568.
Yumiko Katada
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
Sayaka Shimonaka
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
Takashi Temma
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
Hiroyuki Kimura
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
Yasushi Kiyono
- Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan
Chiaki Yokota
- Cerebrovascular Laboratory, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
Kazuo Minematsu
- Cerebrovascular Division, Department of Medicine, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
Koh-ichi Seki
- Central Institute of Isotope Science, Hokkaido University, Hokkaido 060-8638, Japan
Nagara Tamaki
- Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Hokkaido 060-8638, Japan
Kazue Ohkura
- Department of Radiopharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido 061-0293, Japan
Hideo Saji
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan

Received 26 August 2005; received in revised form 30 September 2005; accepted 5 October 2005.

Abstract

Although several COX-2 inhibitors have recently been radiolabeled, their potential for imaging COX-2 expression remains unclear. In particular, the sulfonamide moiety of COX-2 inhibitors may cause slow blood clearance of the radiotracer, due to its affinity for carbonic anhydrase (CA) in erythrocytes. Thus, we designed a methyl sulfone-type analogue, 5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole (IMTP). In this study, the potential of radioiodinated IMTP was assessed in comparison with a ¹²⁵I-labeled celecoxib analogue with a sulfonamide moiety (¹²⁵I-IATP).

Methods

The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of ¹²⁵I-IMTP and ¹²⁵I-IATP was determined by the ex vivo tissue counting method in rats. Distribution of the labeled compounds to rat blood cells was measured.

Results

The COX-2 inhibitory potency of IMTP (IC₅₀=5.16 μM) and IATP (IC₅₀=8.20 μM) was higher than that of meloxicam (IC₅₀=29.0 μM) and comparable to that of SC-58125 (IC₅₀=1.36 μM). The IC₅₀ ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of ¹²⁵I-IMTP and ¹²⁵I-IATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of ¹²⁵I-IMTP was much faster than that of ¹²⁵I-IATP. Distribution of ¹²⁵I-IATP to blood cells (88.0%) was markedly higher than that of ¹²⁵I-IMTP (18.1%), which was decreased by CA inhibitors.

Conclusions

Our results showed a high inhibitory potency and selectivity of IMTP for COX-2. The substitution of a sulfonamide moiety to a methyl sulfone moiety effectively improved the blood clearance of the compound, indicating the loss of the cross reactivity with CA in ¹²⁵I-IMTP. ¹²³I-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression.

Keywords: Cyclooxygenase-2 (COX-2), Inhibitor, Radioiodination, SPECT, Radiopharmaceutical