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

Synthesis of [C-11] celecoxib, a selective COX-2 inhibitor, and [C-11]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 [C-11] celecoxib was achieved in one-pot by reacting [C-11] methyl iodide with an excess of the corresponding pinacol borate precursor using Pd-2(dba)(3), P(o-tolyl)(3), and K2CO3 (1:4:9) in DMF. The radiochemical yield of [C-11] celecoxib was 63 +/- 23% (decay-corrected, based on [C-11] CH3I) (n = 7) with a specific radioactivity of 83 +/- 23 GBq/mu mol (n = 7). The average time of synthesis from end of bombardment including formulation was 30 min with > 99% radiochemical purity. [C-11] SC-62807 was synthesized from [C-11] celecoxib by further rapid oxidation in the presence of excess KMnO4 with microwave irradiation. The radiochemical yield of [C-11] SC-62807 was 55 +/- 9% (n = 3) (decay-corrected, based on [C-11] celecoxib) with a specific radioactivity of 39 +/- 4 GBq/mu mol (n = 3). The average time of synthesis from [C-11] celecoxib including formulation was 20 min and the radiochemical purity was > 99%. PET studies in rats and the metabolite analyzes of [C-11] celecoxib and [C-11] SC-62807 showed largely different excretion processes, and consequently, [C-11] SC-62807 was rapidly excreted via hepatobiliary excretion without further metabolism. [C-11] SC-62807 was shown to have a high potential as a PET probe for evaluating drug transporter function in biliary excretion. (C) 2011 Elsevier Ltd. All rights reserved.