Antiestrogens and antiestrogen metabolites: preparation of tritium-labeled (.+-.)-cis-3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol and characterization and synthesis of a biologically important metabolite

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Abstract
The Upjohn antiestrogen (2b, U 23469) was prepared in 3H-labeled form by reduction of an unsaturated dihydronaphthalene precursor with carrier-free 3H gas over a Pd catalyst followed by alkylation with 3-iodo-1,2-propanediol. After extensive chromatographic purification, the final material was obtained with a specific activity of 13 Ci/mmol and a radiochemical purity of 94%. In vivo studies with immature rats show that [3H]2b is slowly converted to a more polar metabolite that is selectively accumulated in the nuclear fraction of the uterus where it is bound to the estrogen receptor. Chromatographic comparisons indicate that this metabolite is the demethylated analog 2c, a compound that has an affinity for estrogen receptor more than 300 times greater than that of 2b. The demethylated analog 2c may be a biologically important metabolite of 2b that is involved in the action of this antiestrogen.

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