ABSTRACT
16 alpha-[77 Br]-Bromoestradiol-17 beta (3a) has been synthesized from estrone enol diacetate (1) by bromination with Na77Br and hydrogen peroxide-acetic acid, followed by reduction with lithium aluminum hydride to give a mixture of 16 alpha-[77 Br]-bromoestradiol-17 beta (3a) and 16 alpha-[77Br]-bromoestradiol-17 alpha (3b) from which the desired epimer (3a) can be obtained in 50% overall radiochemical yield (from Na77Br) by HPLC. Analogous procedures can be used in the preparation of 16 alpha-[77Br]-bromo-11 beta-methoxyestradiol-17 beta. (4a) The effective specific activities of these radiopharmaceuticals, determined by binding to the uterine estrogen receptor, are 900-1500 Ci/mmol. Both have affinity and good binding selectivity for the estrogen receptor and are useful as imaging agents for mammary tumors.
Subject(s)
Bromine , Estradiol/analogs & derivatives , Radioisotopes , Receptors, Estrogen/metabolism , Animals , Estradiol/chemical synthesis , Female , Isotope Labeling , Neoplasms, Hormone-Dependent/diagnostic imaging , Protein Binding , Radionuclide Imaging , Sheep , Uterus/metabolismABSTRACT
16 alpha[77Br]Bromo-11 beta-methoxyestradiol-17 beta [MBE(Br-77)], a compound with high affinity for the estrogen receptor and with low nonspecific binding, has been prepared with an effective specific activity of 770--1450 Ci per mmole at the time of synthesis. In immature female rats, this compound is taken up selectively by the uterus and is retained for prolonged periods. This is presumably due to the binding of this compound to the estrogen receptor, as uterine uptake is blocked selectively by coadministration of an excess of unlabeled estradiol, and administration of a chase dose of unlabeled estradiol results in a rapid decrease in activity in the uterus. In double-label experiments with 16 alpha[125I]estradiol and MBE(Br-77), the two compounds showed equally selective uterine uptake at 1 hr, but the bromine-labeled compound became increasingly more selective at 3 and 6 hr. MBE(Br-77) may prove to be a more favorable agent for imaging human breast tumors than our previously described compound, 16 alpha-[77Br]bromoestradiol-17 beta.
Subject(s)
Bromine , Estradiol/analogs & derivatives , Radioisotopes , Animals , Breast Neoplasms/diagnostic imaging , Female , Humans , Macaca nemestrina , Radiation Dosage , Radionuclide Imaging , Rats , Rats, Inbred Strains , Receptors, Estrogen/metabolism , Time Factors , Tissue Distribution , Uterus/metabolismABSTRACT
An in vivo comparison of two estrogen-receptor-binding radiopharmaceuticals of high specific activity, 16 alpha-[77Br]bromoestradiol-17 beta and 16 alpha-[125I]iodoestradiol-17 beta, has been carried out in immature female rats. The iodoestradiol has slightly higher uterine uptake at 1 hr after injection, whereas the brominated analog has significantly enhanced uptake at later times. The similar behavior of the two compounds in vivo suggests that estradiol labeled with I-123, Br-77, or Br-75 could be used interchangeably for the imaging of breast tumors containing estrogen receptors. In addition, coinjection of 16 alpha-[125I]iodoestradiol as an internal standard has been shown to be useful for comparison of different radiohalogenated estrogens.
Subject(s)
Bromine , Estradiol/analogs & derivatives , Iodine Radioisotopes , Radioisotopes , Animals , Breast Neoplasms/diagnostic imaging , Female , Humans , Radionuclide Imaging , Rats , Rats, Inbred Strains , Receptors, Estrogen/metabolism , Thyroid Gland/metabolism , Time Factors , Uterus/metabolismABSTRACT
An estrogen-receptor-binding radiopharmaceutical, 16 alpha-[77Br]bromoestradiol-17 beta, has been used successfully at high specific activity to image carcinogen-induced mammary tumors in rats and in preliminary studies to image breast tumors in patients. The biodistribution of the labeled estrogen in rats and its clearance in a monkey were used to estimate the radiation absorbed doses to a human resulting from administration of the radiopharmaceutical. Preliminary imaging studies in patients with mammary carcinoma show promising results and warrant further development of radiolabeled estrogens, particularly those carrying positron emitters that could permit positron emission tomography--for example Br-75 or F-18.
Subject(s)
Bromine , Estradiol/analogs & derivatives , Radioisotopes , Animals , Breast Neoplasms/diagnostic imaging , Female , Humans , Macaca nemestrina , Mammary Neoplasms, Experimental/diagnostic imaging , Radiation Dosage , Radionuclide Imaging , Rats , Rats, Inbred Strains , Receptors, Estrogen/metabolism , Tissue DistributionABSTRACT
16 alpha-[77Br]Bromoestradiol-17 beta (Compound 1) has been synthesized by radiobromination of estrone enoldiacetate. Tissue uptake studies performed 1 hr after administration of Compound 1 to immature or mature female rats showed uterus-to-blood ratios of 13, with nontarget issue-to-blood ratios ranging from 0.6 to 2. Co-administration of unlabelled estradiol caused a selective depression in the uterine uptake with no effect on nontarget tissue uptake. In adult animals bearing adenocarcinomas induced by DMBA (7,12-dimethylbenz(a)anthracene), tumor-to-blood ratios of 6.3 were obtained, this uptake also being depressed in animals treated with unlabeled estradiol. The studies demonstrate that Compound 1 has suitable binding properties and sufficiently high specific activity so that its uptake in estrogen target tissues in vivo is mediated primarily by the estrogen receptor. Furthermore, they suggest that this compound may be suitable for imaging human breast tumors that contain estrogen receptors.
Subject(s)
Bromine , Estradiol , Mammary Neoplasms, Experimental/metabolism , Steroids, Brominated , Uterus/metabolism , 9,10-Dimethyl-1,2-benzanthracene , Animals , Estradiol/chemical synthesis , Female , Mammary Neoplasms, Experimental/chemically induced , Radioisotopes , Rats , Receptors, Estrogen/metabolism , Steroids, Brominated/chemical synthesis , Tissue DistributionABSTRACT
Steroidal and nonsteroidal estrogens substituted with halogens ortho to the phenolic hydroxyl group in the D ring at C-16 have been prepared as potential estrogen receptor-based imaging agents for human breast tumors. Estrogens bearing an aromatic fluorine ortho to a phenolic hydroxyl group were prepared by the Schiemann reaction on the corresponding methyl esters; other ortho-halogenated estrogens were prepared by direct halogenation. Steroidal estrogens substituted at the 16 alpha position were prepared by halogenation of estrone 3-acetate (17-enol acetate) followed by hydride reduction, and those substituted at the 16 beta position were prepared by epimerization prior to reduction. The binding affinity of these halogenated estrogens to the uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. All of the monosubstituted ortho-fluorinated estrogens show very high binding affinity for the receptor (64--250% that of estradiol). The monosubstituted and symmetrically disubstituted bromo- and iodohexestrols and 2- and 4-substituted estradiols have binding affinities considerably lower than those of the fluoro compounds, the 4-substituted estradiols have affinities greater than the corresponding 2-substituted isomers. Introduction of a halogen (Cl, Br, I) at the 16 alpha position of 17 beta-estradiol results in compounds with receptor affinities comparable to that of 17 beta-estradiol itself; the 16 beta-epimers and the estrone derivatives are bound less well. Thus, provided that they can be labeled with suitable gamma-emitting radioisotopes at sufficiently high specific activity, it appears that the A-ring fluoroestrogens and 16 alpha-bromo- and 16 alpha-iodoestradiol-17 beta are excellent candidates for receptor-based imaging of human breast tumors.