title: 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 [(11)C]methyl iodide. The obtained radiochemical yield was 20-30%. The specific activity was determined to be 20-40GBq/micromol at the end-of-synthesis, and the radiochemical purity exceeded 98%.
authors.affiliation: Institut für Radiopharmazie, Forschungszentrum Dresden-Rossendorf e.V., Postfach 510119, 01314 Dresden, Germany. f.wuest@fzd.de
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D001667:Binding, Competitive; D002250:Carbon Radioisotopes; D003907:Dexamethasone / Q000737:chemistry / Q000378:metabolism; D005938:Glucocorticoids / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013256:Steroids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D013256:Steroids; D003907:Dexamethasone