P07 - Non-PET chemistry

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: French
• Weight: 499 KB
• Volume: 48
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.987

✦ Synopsis

Cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid into prostaglandins and thoromboxanes. COX-2, an inducible isoform of the enzyme, has been implicated in a number of pathologic processes, including many human cancers, atheroscrelosis, and cerebral and cardiac ischemia. In this regard, non-invasive imaging of COX-2 expression should help understand the pathophysiology of the diseases and contribute to the clinical use of the COX-2 inhibitors. However, only a few attempts have been reported on the radiosynthesis of COX-2 inhibitors as in vivo imaging agents. Thus, we intended to develop a radioiodinated coxib as a SPECT tracer for imaging COX-2 expression and designed 5- (Figure). In this study, radioiodinated IMTP was synthesized and its potential was assessed.

Methods: IMTP and 5-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole (BMTP) were synthesized according to the procedure outlined in Figure . Briefly, compound 2 was synthesized by a Claisen condensation of compound 1 and ethyltrifluoroacetate. The product 2 was reacted with 4-methylsulfonylhydrazine hydrochloride to obtain IMTP and BMTP. The radioiodinated IMPT was obtained by a halogen exchange reaction with sodium 125 I-iodine, and purified with a reverse-phase high-performance liquid chromatography. COX inhibitory potency of IMTP was assessed using a commercially available kit (Colorimetric COX Inhibitor Screening Assay Kit, Cayman Chemical) according to the manufacturer's instructions. SC-58125, meloxicam, and indomethacin were used as reference compounds.

Results and Discussion: IMPT and BMTP were obtained with the yields of 18% and 25% from the starting material 1, respectively. The radiosynthesis of 125 I-IMTP was achieved with an iodine-bromide exchange reaction. Following separation from the precursor BMTP, 125 I-IMTP was obtained with no carrier-being added. The radiochemical yield was 42%, and the radiochemical purity was greater than 95%.

IMTP inhibited COX-2 in a concentration dependent manner, while it showed no inhibitory potency for COX-1 at the concentrations up to 100 µM. The IC 50 values of IMTP were 5.16 µM for COX-2 and > 100 µM for COX-1. The COX-2 inhibitory potency of IMTP was higher than that of meloxicam (IC 50 =29.0 µM) and comparable to that of SC-58125 (IC 50 =1.36 µM), a potent COX-2 selective inhibitor. The IC 50 ratio (COX-1/COX-2) for IMTP, meloxicam, and SC-58125 were more than 19, 3.5, and 73, indicating a high isoform selectivity of IMTP for COX-2.

Conclusion: A radioiodinated coxib, 125 I-IMTP was synthesized. Our results showed a high inhibitory potency and selectivity of IMTP for COX-2, indicating its potential as a SPECT tracer for imaging cyclooxygenase-2 expression.