Synthesis of Stable Isotope-Labeled Steroids as Internal Standards

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Our goal is to regiospecifically synthesize stable-isotope labeled steroids for use in liquid chromatography-mass spectroscopy (LC-MS) assays for endogenous steroid hormones such estrogens, androgens, and progestogens that are believed to play critical roles in various cancers (such as breast, endometrial, ovarian and prostate). The long term goal of this work is to develop synthetic methodology for estrone, estradiol and progesterone derivatives that is both reproducible, and that gives high purity isotopically labeled steroids with the isotopes incorporated at non-exchangeable positions. The research in this proposal is designed to verify our methodology by examining various synthetic alternatives in order to meet the criteria of a reproducible synthesis, placement of the stable isotope labels at non-exchangeable positions such that the steroids are labeled to at least M+3, in a good to high yielding overall process. The long term goal is to scale up the chemical syntheses of these stable isotope-labeled steroids and combine them in one or more kits. These stable isotope standards will permit academic and clinical laboratories to establish sensitive, accurate LC-MS method~ for measuring endogenous steroid hormones in biologic samples and to standardize the measurements across laboratories.