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

Frank Wuest, Kathryn E. Carlson, John A. Katzenellenbogen

Research output: Contribution to journalArticlepeer-review

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 20-40 GBq/μmol at the end-of-synthesis, and the radiochemical purity exceeded 98%.

Original languageEnglish (US)
Pages (from-to)69-76
Number of pages8
JournalSteroids
Volume73
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Carbon-11
  • Glucocorticoid receptor binding
  • Mitsunobu reaction
  • Positron-emission-tomography (PET)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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