Skip to main content
SpringerLink
Log in

The stereoisomers of 17α-[123I]iodovinyloestradiol and its 11α-methoxy derivative evaluated for their oestrogen receptor binding in human MCF-7 cells and rat uterus, and their distribution in immature rats

  • Original Article
  • Published:
European Journal of Nuclear Medicine Aims and scope Submit manuscript

Abstract

We studied the potential of both stereoisomers of 17α-[123I]iodovinyloestradiol (E- andZ-[123I]IVE) and of 11β-methoxy-17α-[123I]iodovinyloestradiol (E-andZ-[123I]MIVE) as suitable radioligands for the imaging of oestrogen receptor(ER)-positive human breast tumours. The 17α-[123I]iodovinyloestradiols were prepared stereospecifically by oxidative radio-iododestannylation of the corresponding 17α-tri-n-butylstannylvi-nyloestradiol precursors. Competitive binding studies were performed in order to determine the relative binding affinity (RBA) of the unlabelled 17α-iodovinyloes-tradiols for the ER in both human MCF-7 breast tumour cells and rat uterine tissue, compared with that of diethylstilboestrol (DES). Target tissue uptake, retention and uptake selectivity of their123I-labelled analogues were studied in immature female rats. All four 17α-iodovi-nyloestradiols showed high affinity for the ER in human MCF-7 cells, as well as rat uterus. Their RBA for the ER showed the following order of decreasing potency: RBA of DES >Z-IVE >Z-MIVE >E-MIVE ≥E-IVE. Neither of these 17α-iodovinyloestradiols showed any significant binding to the sex hormone binding globulin in human plasma. The biodistribution studies showed ER-mediated uptake in the uterus, ovaries and pituitary, that ofE- andZ-[123I]MIVE being higher than that ofE- andZ-[123I]IVE. High target-to-non-target tissue uptake ratios, especially at longer periods after injection (up to 24 h), were exhibited by both isomers of [123I]MIVE. The uterus-to-blood uptake ratio was higher forE-[123I]MIVE. However, the uterus-to-fat uptake ratio appeared to be higher for theZ-isomer of [123I]MIVE, especially at 24 h after injection. Metabolic properties and temperature effects, which play a more important role in vivo, probably cause the discrepancies seen between in vitro and in vivo binding results. On the basis of their in vitro binding properties and in vivo distribution characteristics we conclude thatE- andZ-[123I]MIVE could be suitable radioligands for the diagnostic imaging of ER in human breast cancer. Therefore, further studies with these radioligands in mature normal and tumour-bearing rats are warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. De Waard F. Epidemiology of breast cancer; a review.Eur J Cancer Clin Oncol 1983; 19: 1671–1676.

    PubMed  Google Scholar 

  2. Van Bon-Martens MJH, Verbeek ALM, Peeters PHM, Luning P, Werre JM. Een overzicht van de epidemiologie van borstkanker in Nederland.Ned Tijdschr Geneeskd 1990; 134: 287–291.

    PubMed  Google Scholar 

  3. Allegra JC, Lippman ME, Thompson EB, Simon R, Barlock A, Green L, Huff KK, Do HMT, Aitken SC, Warren R. Estrogen receptor status: an important variable in predicting response to endocrine therapy in metastatic breast cancer.Eur J Cancer 1980; 16: 323–331.

    PubMed  Google Scholar 

  4. McGuire WL, Horwitz KB, Pearson OH, Segaloff A. Current status of estrogen and progesterone receptors in breast cancer.Cancer 1977; 39: 2934–2947.

    PubMed  Google Scholar 

  5. Clark GM, Sledge GW Jr, Osborne CK, McGuire WL. Survival from first recurrence: relative importance of prognostic factors in 1.015 breast cancer patients.J Clin Oncol 1987; 5: 55–61.

    PubMed  Google Scholar 

  6. Donegan WL. Prognostic factors; stage and receptor status in breast cancer.Cancer 1992; 70: 1755–1764.

    PubMed  Google Scholar 

  7. Van Netten JP, Armstrong JB, Carlyle SS, Goodchild NL, Thornton IG, Brigden ML, Coy P, Fletcher C. Estrogen receptor distribution in the peripheral, intermediate, and central regions of breast cancers.Eur J Cancer Clin Oncol 1988; 24: 1885–1889.

    PubMed  Google Scholar 

  8. Holdaway IM, Bowditch JV. Variation in receptor status between primary and metastatic breast cancer.Cancer 1983; 52: 479–485.

    PubMed  Google Scholar 

  9. Mobbs BG, Fisch EB, Pritchard KI, Oldfield G, Hanna WH. Estrogen and progesterone receptor content of primary and secondary breast carcinoma: influence of time and treatment.Eur J Cancer Clin Oncol 1987; 23: 819–826.

    PubMed  Google Scholar 

  10. Eckelman WC, Reba RC. Labeled estrogens and analogues. In: Spencer RP, ed.Radiopharmaceuticals: structure-activity relationships. New York: Grune and Stratton; 1981: 449–458.

    Google Scholar 

  11. Katzenellenbogen JA, Carlson KE, Hetman DF, Lloyd JE. Receptor binding as a basis for radiopharmaceutical design. In: Spencer RP, ed.Radiopharmaceuticals: structure-activity relationships. New York: Grune and Stratton; 1981: 23–86.

    Google Scholar 

  12. Hochberg RB. Iodine-125-labeled estradiol: a gamma-emitting analog of estradiol that binds to the estrogen receptor.Science 1979; 205: 1138–1140.

    PubMed  Google Scholar 

  13. Hanson RN, Seitz DE, Botarro JC.E-17α-[125I]iodovinyles-tradiol: an estrogen-receptor-seeking radiopharmaceutical.J Nucl Med 1982; 23: 431–436.

    PubMed  Google Scholar 

  14. Hanson RN, Franke LA. Preparation and evaluation of 17α-[125I]iodovinyl-11(β-methoxyestradiol as a highly selective radioligand for tissues containing estrogen receptors: concise communication.J Nucl Med 1984; 25: 998–1002.

    PubMed  Google Scholar 

  15. Katzenellenbogen JA, Carlson KE, Heiman DF, Goswami R. Receptor-binding radiopharmaceuticals for imaging breast tumours: estrogen receptor interactions and selectivity of tissue uptake of halogenated estrogen analogs.J Nucl Med 1980; 21: 550–558.

    PubMed  Google Scholar 

  16. Kiesewetter DO, Kilbourn MR, Landvatter SW, Heiman DF, Katzenellenbogen JA, Welch MJ. Preparation of four fluorine-18-labeled estrogens and their selective uptakes in target tissues in immature rats.J Nucl Med 1984; 25: 1212–1221.

    PubMed  Google Scholar 

  17. Feenstra A, Nolten GMJ, Vaalburg W Reiffers S, Woldring MG. Radiotracers binding to estrogen receptors: I: tissue distribution of 17α-ethynylestradiol and moxestrol in normal and tumor-bearing rats.J Nucl Med 1982; 23: 599–605.

    PubMed  Google Scholar 

  18. Katzenellenbogen JA, Johnson HJR, Myers HN. Photoaffinity labels for estrogen binding proteins of rat uterus.Biochemistry 1973, 12: 4085–4092.

    PubMed  Google Scholar 

  19. Landvatter SW, Katzenellenbogen JA, McElvany KD, Welch MJ. (2R *,3S *)-1-[125I]iodo-2,3-bis(4-hydroxyphenyl)pentane ([125I]iodonorhexestrol) and (2R *,3S *)-1-[77Br]bromo-2,3-bis (4-hydroxyphenyl)pentane ([77Br]bromonorhexestrol), two gamma-emitting estrogens that show receptor-mediated uptake by target tissues in vivo.J Med Chem 1982; 25: 1307–1312.

    PubMed  Google Scholar 

  20. Hochberg RB, Rosner W. Interaction of 16α-[125I]iodo-estra-diol with estrogen receptor and other steroid-binding proteins.Proc Natl Acad Sci USA 1980; 77: 328–332.

    PubMed  Google Scholar 

  21. Lippman ME, Do HMT, Hochberg RB. Specific estrogen receptor binding and biological effects of 16α,-iodoestradiol on human breast cancer cells.Cancer Res 1981; 41: 3150–3154.

    PubMed  Google Scholar 

  22. McElvany KD, Carlson KE, Welch MJ, Senderoff SG, Katzenellenbogen JA, the Los Alamos Medical Radioisotope Group. In vivo comparison of 16α-[77Br]bromoestradiol-l7α and 16α-[125I]iodoestradiol-l7β.J Nucl Med 1982; 23: 420–424.

    PubMed  Google Scholar 

  23. Jagoda EM, Gibson RE, Goodgold H, Ferreira N, Francis BE, Reba RC, Rzeszotarski WJ, Eckelman WC. [I-125] 17α-iodo-vinyl 11β-methoxyestradiol: in vivo and in vitro properties of a high-affinity estrogen-receptor radiopharmaceutical.J Nucl Med 1984; 25: 472–477.

    PubMed  Google Scholar 

  24. Nakatsuka I, Ferreira NL, Eckelman WC, Francis BE, Rzeszotarski WJ, Gibson RE, Jagoda EM, Reba RC. Synthesis and evaluation of (17α, 20E)-21-[125I]iodo-19-norpregna 1,3,5(10),20-tetraene-3,17-diol and (17α, 20E)-21-[125I]iodo-11β-methoxy-19-norpregna-1,3,5 (10),20-tetraene-3,17-diol (17α-(iodovinyl)estradiol derivatives) as high specific activity potential radiopharmaceuticals.J Med Chem 1984; 27: 1287–1291.

    PubMed  Google Scholar 

  25. Mintun MA, Welch MJ, Siegel BA, Mathias CJ, Brodack JW, McGuire AHM, Katzenellenbogen JA. Breast cancer: PET imaging of estrogen receptors.Radiology 1988; 169: 45–48.

    PubMed  Google Scholar 

  26. McGuire AH, Dehdashti F, Siegel BA, Lyss AP, Brodack JW, Mathias CJ, Mintun MA, Katzenellenbogen JA, Welch MJ. Positron tomographic assessment of 16α-[18F]fluoro-l7β-es-tradiol uptake in metastatic breast carcinoma.J Nucl Med 1991; 32: 1526–1531.

    PubMed  Google Scholar 

  27. Preston DF, Spicer JA, Baranczuk RA, Fabian C, Baxter KG, Martin NL, Robinson RG. Clinical results of breast cancer detection by imageable estradiol (1-123 E2 ).Eur J Nucl Med 1990; 16: 430.

    Google Scholar 

  28. Schober O, Scheidhauer K, Jackisch C, Schicha H, Smolarz K, Bolte A, Reiners C, Höffken K, Biersack HJ, Briele B, Moser E, Bräutigam P. Breast cancer imaging with radioiodinated oestradiol.Lancet 1990; 335: 1522.

    Google Scholar 

  29. Scheidhauer K, Müller S, Smolarz K, Bräutigam P, Briele B. Tumor-szintigraphie mit123J-markiertem Östradiol beim Mammakarzinom-Rezeptorszintigraphie.Nucl-Med 1991; 30: 84–99.

    Google Scholar 

  30. Gatley SJ, Shaughnessy WJ, Inborn L, Lieberman LM. Studies with 17β(16α-[125I]iodo)-estradiol, an estrogen receptor-binding radiopharmaceutical, in rats bearing mammary tumours.J Nucl Med 1981; 22: 459–464.

    PubMed  Google Scholar 

  31. Symes EK, Coulson WF, Ralphs DNL. The synthesis of 16α-[131I]iodo-oestradiol and evaluation of its use as a radiotracer for oestrogen receptor positive breast tumours.J Steroid Biochem 1985; 22: 155–160.

    PubMed  Google Scholar 

  32. Katzenellenbogen JA, McElvany KD, Senderoff SG, Carlson KE, Landvatter SW, Welch MJ, the Los Alamos Radioisotope Group. 16α-[77Br]bromo-1lβ-methoxyestradiol-17β: a gamma-emitting estrogen imaging agent with high uptake and retention by target organs. J Nucl Med 1982; 23: 411–419.

    PubMed  Google Scholar 

  33. Zielinski JE, Larner JM, Hoffer PB, Hochberg RB. The synthesis of 11β-methoxy-[16α-123I]iodoestradiol and its interaction with the estrogen receptor in vivo and in vitro. J Nucl Med 1989; 30: 209–215.

    PubMed  Google Scholar 

  34. Hanson RN, Franke LA, Kaplan ML. Synthesis and evaluation of (17α, 20E)21-[125I]iodo-11-substituted-l9-norpregna-1,3,5 (10),20-tetraene-3,17β-diols: the influence of 11-stereochemistry on tissue distribution of radioiodinated estrogens.Nucl Med Biol 1989; 16: 3–9.

    Google Scholar 

  35. Quivy J, Delcorde A, Henrot P, Deblaton M, Pirotte R, Verbist A, Frühling J, Zeicher M. New steroidal agent with high selectivity for the radioimaging of tumour tissues containing estrogen receptors.Eur J Nucl Med 1990; 16: 430.

    Google Scholar 

  36. Ali H, Rousseau J, Ghaffari MA, Van Lier JE. Synthesis, receptor binding, and tissue distribution of 7α- and 11β-substituted (17α, 20E)- and (17α, 20Z)-21-[125I]iodo-19-norpregna 1,3,5(10),20-tetraene-3,17-diols.J Med Chem 1991; 34: 854–860.

    PubMed  Google Scholar 

  37. Hanson RN, Ghoshal M, Murphy FG, Rosenthal C, Gibson RE, Ferriera N, Sood V, Ruch J. Synthesis, receptor binding and tissue distribution of 17α-E[125I]iodovinyl-11β-ethyl-estradiol.Nucl Med Biol 1993; 20: 351–358.

    PubMed  Google Scholar 

  38. Ali H, Rousseau J, Van Lier JE. Synthesis of A-ring fluorinated derivatives of (17α, 20E/Z)-[125I]iodovinylestradiols: effect on receptor binding and receptor-mediated target tissue uptake.J Med Chem 1993; 36: 3061–3072.

    PubMed  Google Scholar 

  39. Ribeiro-Barras MJ, Foulon C, Baulieu JL, Guilloteau D, Bougnoux P, Lansac J, Besnard JC. Estrogen receptor imaging with 17α-[123I]iodovinyl-11β-methoxyestradiol (MIVE2). Part II. Preliminary results in patients with breast carcinoma.Nucl Med Biol 1992; 19: 263–267.

    Google Scholar 

  40. Foulon C, Guilloteau D, Baulieu JL, Ribeiro-Barras MJ, Desplanches G, Frangin Y, Besnard JC. Estrogen receptor imaging with 17α-[123I]iodovinyl-11β-methoxyestradiol (MIVE2). Part I. Radiotracer preparation and characterization.Nucl Med Biol 1992; 19: 257–261.

    Google Scholar 

  41. Napolitano E, Fiaschi R, Hanson RN. Structure-activity relationships of estrogenic ligands: synthesis and evaluation of (17α, 20E)- and (17α, 20Z)-21-halo-19-norpregna-1,3,5(10), 20-tetraene-3,17β-diols.J Med Chem 1991; 34: 2754–2759.

    PubMed  Google Scholar 

  42. McManaway ME, Jagoda EM, Eckelman WC, Larson SM, Francis BE, Gibson RE, Reba RC, Lippman ME. Binding characteristics and biological activity of 17α-[125I]-11(β-methoxyestradiol, an estrogen receptor-binding radiopharmaceutical, in human breast cancer cells (MCF-7).Cancer Res 1986; 46: 2386–2389.

    PubMed  Google Scholar 

  43. Souttou B, Moretti J-L, Gros J, Guilloteau D, Crepin M. Receptor binding and biological effects of three125I-iodinated estrogen derivatives in human breast cancer cells (MCF-7).J Steroid Biochem Mol Biol 1993; 44: 105–112.

    PubMed  Google Scholar 

  44. McElvany KD, Carlson KE, Katzenellenbogen JA, Welch MJ. Factors affecting the target site uptake selectivity of estrogen radiopharmaceuticals: serum binding and endogenous estrogens.J Steroid Biochem 1983; 18: 635–641.

    PubMed  Google Scholar 

  45. Hanson RN, Franke LA, Kaplan M. Radioiodinated ligands for the estrogen receptor: tissue distribution of 17α-[125I]iodo-vinylestradiol derivatives in normal and tumor-bearing adult female rats.Nucl Med Biol 1990; 17: 239–245.

    Google Scholar 

  46. Merrick MV, Corrie JET, Millar AM, Hawkins RA. A reevaluation of an agent proposed for imaging oestrogen receptors: 17α-[125I]iodovinyl-11β-methoxyoestradiol-3-methyl ether ([125I]VMEME).Nucl Med Biol 1988; 15: 327–332.

    Google Scholar 

  47. Hughes A, Gatley SJ, DeSombre ER. Comparison of the distribution of radioiodinated-E-17α-iodovinyl-11β-methoxyestradiol and 2-iodo-1,1-bis(4-hydroxyphenyl)-phenylethylene estrogens in the immature female rat.J Nucl Med 1993; 34: 272–280.

    PubMed  Google Scholar 

  48. Hoyte RM, Rosner W, Johnson IS, Zielinski J, Hochberg RB. Synthesis and evaluation of potential radioligands for the progesterone receptor. J Med Chem 1985; 28: 1695–1699.

    PubMed  Google Scholar 

  49. Ali H, Rousseau J, Ghaffari MA, Van Lier JE. Synthesis, receptor binding, and tissue distribution of (17α, 20E)- and (17α, 20Z)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetene-3,17-diol.J Med Chem 1988; 31: 1946–1950.

    PubMed  Google Scholar 

  50. Witsenboer AJ, De Goeij JIM, Reiffers S. Production of iodine-123 via proton irradiation of 99.8% enriched xenon-124.J Lab Comp Radiopharm 1986; 23: 1284–1285.

    Google Scholar 

  51. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.Anal Biochem 1976; 72: 248–254.

    Article  PubMed  Google Scholar 

  52. Munson PJ, Rodbard D. Ligand: a versatile computerized approach for characterization of ligand binding systems.Anal Biochem 1980; 107: 220–239.

    PubMed  Google Scholar 

  53. Feenstra MGP, Snijdewint FGM, Van Galen H, Boer GJ. Widespread alterations in central noradrenaline, dopamine and serotonin systems in the Brattleboro rat not related to the local absence of vasopressin.Neurochem Res 1990; 15: 283–288.

    PubMed  Google Scholar 

  54. Raynaud JP, Bouton M-M, Gallet-Bourquin D, Philibert D, Tournemine C, Azadian-Boulanger G. Comparative study of estrogen action.Mol Pharmacol 1973; 9: 520–533.

    PubMed  Google Scholar 

  55. Pomper MG, VanBrocklin H, Thieme AM, Thomas RD, Kiesewetter DO, Carlson KE, Mathias CJ, Welch MJ, Katzenellenbogen JA. 11 β-methoxy-, 11β-ethyl- and 17α-ethynyl-sub-stituted 16α-fluoroestradiols: receptor-based imaging agents with enhanced uptake efficiency and selectivity.J Med Chem 1990; 33: 3143–3155.

    PubMed  Google Scholar 

  56. Symes EK, Bishop PB, Coulson WF, Davies AG. 17α-Z-[123I]iodovinyloestradiol and its 3-acetate: chemical synthesis and in vivo distribution studies in the rat; comparison of tissue accumulation and metabolic stability with 17α-E-[125I]iodovinyl and 16α-[125I]iodo oestradiols.Biochem Pharmacol 1992; 44: 741–746.

    PubMed  Google Scholar 

  57. Dionne FT, Lesage RL, Dubé JY, Tremblay RR. Estrogen binding proteins in rat skeletal and perineal muscles: in vitro and in vivo studies.J Steroid Biochem 1979; 11: 1073–1080.

    PubMed  Google Scholar 

  58. Gray JM, Dudley SD, Wade GN. In vivo cell nuclear binding of 17 beta- [3H]-estradiol in rat adipose tissues.Am J Physiol 1981; 240: E43-E46.

    PubMed  Google Scholar 

  59. Salmon J, Coussediere D, Cousty C, Raynaud JP. Pharmacokinetics and metabolism of moxestrol in animals (rat, dog, monkey).J Steroid Biochem 1983; 19: 1223–1234.

    PubMed  Google Scholar 

  60. VanBrocklin HF, Carlson KE, Katzenellenbogen JA, Welch MJ. 16β-([18F]fluoro)estrogens: systematic investigation of a new series of fluorine-18-labeled estrogens as potential imaging agents for estrogen-receptor-positive breast tumors.J Med Chem 1993; 36: 1619–1629.

    PubMed  Google Scholar 

  61. VanBrocklin HF, Rocque PA, Lee HV, Carlson KE, Katzenellenbogen JA, Welch MJ. 16β-[18F]fluoromoxestrol: a potent, metabolically stable positron emission tomography imaging agent for estrogen receptor positive human breast tumors. Life Sci 1993; 53: 811–819.

    PubMed  Google Scholar 

  62. Katzenellenbogen JA, Mathias CJ, VanBrocklin HF, Brodack JW, Welch MJ. Titration of the in vivo uptake of 16α-[18F]fluoroestradiol by target tissues in the rat: competition by tamoxifen, and implications for quantitating estrogen receptors in vivo and the use of animal models in receptor-binding radiopharmaceutical development.Nucl Med Biol 1993; 20: 735–745.

    PubMed  Google Scholar 

  63. Murono EP, Kirdani RY, Sandberg AA. Specific estradiol-17β binding component in adult rat kidney.J Steroid Biochem 1979; 11: 1347–1351.

    PubMed  Google Scholar 

  64. Morgan DD, Grossman CJ. Analysis and properties of the cytosolic estrogen receptor from rat thymus.Endocr Res 1984; 10: 193–207.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Leonie J. M. Rijks, Kora de Bruin & Eric A. van Royen

  2. Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ, Amsterdam, The Netherlands

    Gerard J. Boer

  3. Department of Endocrinology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands

    Erik Endert

  4. Cygne BV and Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands

    Jan C. van den Bos, Peter A. P. M. van Doremalen & Anton G. M. Janssen

  5. Department of Endocrinology, NV Organon, P.O. Box 20, 5340 BH, Oss, The Netherlands

    Willem G. E. J. Schoonen

Authors
  1. Leonie J. M. Rijks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerard J. Boer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erik Endert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kora de Bruin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jan C. van den Bos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter A. P. M. van Doremalen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Willem G. E. J. Schoonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anton G. M. Janssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eric A. van Royen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rijks, L.J.M., Boer, G.J., Endert, E. et al. The stereoisomers of 17α-[123I]iodovinyloestradiol and its 11α-methoxy derivative evaluated for their oestrogen receptor binding in human MCF-7 cells and rat uterus, and their distribution in immature rats. Eur J Nucl Med 23, 295–307 (1996). https://doi.org/10.1007/BF00837628

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00837628

Key words

Search

Navigation