Expeditious synthesis of steroids containing a 2-methylsulfanyl-acetyl side chain as potential glucocorticoid receptor imaging agents

Abstract: In our effort to develop imaging agents for brain glucocorticoid receptors, we have prepared several novel glucocorticoids possessing a 2-methylsulfanyl-acetyl side chain. The synthesis was accomplished via a Mitsunobu reaction with thiobenzoic acid starting from cortisol, prednisolone, dexamethasone and triamcinolone acetonide to give the corresponding S-thiobenzoates in 75–82% yield. Subsequent saponification and reaction with methyl iodide afforded C-21 methylthioethers in 68–82% yield. All compounds were tested in an in vitro glucocorticoid receptor-binding assay. Triamcinolone acetonide-based compound 12 showed promising binding affinity of 144% relative to dexamethasone (100%). Compound 12 was selected for radiolabeling with the short-lived positron emitter carbon-11. The radiolabeling was carried out starting from S-thiobenzoate 8 and in situ formation of the corresponding sodium thiolate, which was further reacted with [11C]methyl iodide. The obtained radiochemical yield was 20–30%. The specific activity was determined to be 20–40GBq/μmol at the end-of-synthesis, and the radiochemical purity exceeded 98%. [Copyright &y& Elsevier]