Efficient sequential synthesis of PET Probes of the COX-2 inhibitor [ 11C]celecoxib and its major metabolite [ 11C]SC-62807 and in vivo PET evaluation

Abstract

Synthesis of [ 11C]celecoxib, a selective COX-2 inhibitor, and [ 11C]SC-62807, a major metabolite of celecoxib, were achieved and the potential of these PET probes for assessing the function of drug transporter in biliary excretion was evaluated. The synthesis of [ 11C]celecoxib was achieved in one-pot by reacting [ 11C]methyl iodide with an excess of the corresponding pinacol borate precursor using Pd 2(dba) 3, P( o-tolyl) 3, and K 2CO 3 (1:4:9) in DMF. The radiochemical yield of [ 11C]celecoxib was 63 ± 23% (decay-corrected, based on [ 11C]CH 3I) ( n = 7) with a specific radioactivity of 83 ± 23 GBq/μmol ( n = 7). The average time of synthesis from end of bombardment including formulation was 30 min with >99% radiochemical purity. [ 11C]SC-62807 was synthesized from [ 11C]celecoxib by further rapid oxidation in the presence of excess KMnO 4 with microwave irradiation. The radiochemical yield of [ 11C]SC-62807 was 55 ± 9% ( n = 3) (decay-corrected, based on [ 11C]celecoxib) with a specific radioactivity of 39 ± 4 GBq/μmol ( n = 3). The average time of synthesis from [ 11C]celecoxib including formulation was 20 min and the radiochemical purity was >99%. PET studies in rats and the metabolite analyzes of [ 11C]celecoxib and [ 11C]SC-62807 showed largely different excretion processes, and consequently, [ 11C]SC-62807 was rapidly excreted via hepatobiliary excretion without further metabolism. [ 11C]SC-62807 was shown to have a high potential as a PET probe for evaluating drug transporter function in biliary excretion.