Strickland L A, Ponce Y Z, Hunter D H, Zabel P L, Powe J E, Morrissey G, Driedger A A, Chamberlain M J, Tustanoff E R
Department of Chemistry, University of Western Ontario, London, Canada.
Drug Des Deliv. 1990 Sep;6(3):195-212.
Both geometrical isomers (E and Z) of an aminotamoxifen (2) have been prepared as precursors of the corresponding E and Z iodotamoxifens (1). The ability of E and Z-1 and 2 to compete with [3H]estradiol for estrogen receptors in rat uterine cytosol was measured relative to Z-tamoxifen and estradiol. The four tamoxifen derivatives showed affinities ranging from 50% to 1600% of that of tamoxifen. Under the same conditions, tamoxifen's relative binding affinity was 0.2% of that of estradiol. Preparative routes to the radioiodo-tamoxifens, [131I]-E and Z-1, were also developed and provided approximately 100 MBq of 'no carrier added' material in 40-60% radiochemical yield. Study of the biodistribution of these radioligands in tumor-bearing mice demonstrated significant radioactivity in the tumors and in the uterus. For [131I]-E-1, target to background ratios reached 28 for uterus/blood and 10 for tumor/blood; corresponding optimum ratios for [131I]-Z-1 were 10 and 5. A washout study using estradiol indicated selective uptake in the uterus of Swiss white mice. However, tumor uptake and image contrast in humans following intravenous administration of either [131I]-E or Z-1 were insufficient to allow diagnostic use of the radioiodotamoxifens.
已制备了氨基他莫昔芬（2）的两种几何异构体（E型和Z型），作为相应的E型和Z型碘代他莫昔芬（1）的前体。相对于Z型他莫昔芬和雌二醇，测定了E型和Z型-1及2与[3H]雌二醇竞争大鼠子宫胞质溶胶中雌激素受体的能力。这四种他莫昔芬衍生物的亲和力为他莫昔芬的50%至1600%。在相同条件下，他莫昔芬的相对结合亲和力为雌二醇的0.2%。还开发了制备放射性碘代他莫昔芬[131I]-E和Z-1的路线，以40-60%的放射化学产率提供了约100 MBq的“无载体添加”材料。对这些放射性配体在荷瘤小鼠体内生物分布的研究表明，肿瘤和子宫中有明显的放射性。对于[131I]-E-1，子宫/血液的靶本比达到28，肿瘤/血液的靶本比达到10；[131I]-Z-1的相应最佳比值分别为10和5。一项使用雌二醇的洗脱研究表明，瑞士小白鼠的子宫有选择性摄取。然而，静脉注射[131I]-E或Z-1后，人体的肿瘤摄取和图像对比度不足以用于放射性碘代他莫昔芬的诊断。
