Amino and iodotamoxifens: synthesis, estrogen receptor affinity and biodistribution.

Drug design and delivery Pub Date : 1990-09-01
L A Strickland, Y Z Ponce, D H Hunter, P L Zabel, J E Powe, G Morrissey, A A Driedger, M J Chamberlain, E R Tustanoff
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Abstract

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.

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氨基和碘他莫昔芬:合成、雌激素受体亲和力和生物分布。
一个氨基他莫昔芬(2)的几何异构体(E和Z)被制备为相应的E和Z碘他莫昔芬(1)的前体(1)。E和Z-1和2与[3H]雌二醇竞争大鼠子宫细胞质中雌激素受体的能力相对于Z-他莫昔芬和雌二醇进行了测量。四种他莫昔芬衍生物的亲和度为他莫昔芬的50% ~ 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%。还开发了放射性碘-他莫昔芬[131I]-E和Z-1的制备路线,并以40-60%的放射化学产率提供了大约100 MBq的“无载体添加”材料。对这些放射配体在荷瘤小鼠体内的生物分布研究表明,这些放射配体在肿瘤和子宫内有显著的放射性。对于[131I]-E-1,子宫/血液的靶本比为28,肿瘤/血液的靶本比为10;[131I]-Z-1的最佳配比分别为10和5。一项使用雌二醇的洗脱研究表明,雌二醇在瑞士小白鼠的子宫中有选择性摄取。然而,静脉注射[131I]-E或Z-1后的肿瘤摄取和图像对比不足以允许使用放射性碘多莫西芬进行诊断。
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