Progestin radiopharmaceuticals labeled with technetium and rhenium: synthesis, binding affinity, and in vivo distribution of a new progestin N2S2-metal conjugate.
Progestin radiopharmaceuticals labeled with technetium and rhenium: synthesis, binding affinity, and in vivo distribution of a new progestin N2S2-metal conjugate.
复制标题
锝和铼标记的孕激素放射性药物：新型孕激素 N2S2-金属缀合物的合成、结合亲和力和体内分布。
DOI：
10.1021/bc00027a002
复制
发表时间：
1994
影响因子：
4.7
通讯作者：
Katzenellenbogen,JA
中科院分区：
文献类型：
--
作者：
O'Neil,JP;Carlson,KE;Anderson,CJ;Welch,MJ;Katzenellenbogen,JA
我们制备并评估了孕激素-单胺-单酰胺（MAMA'）双硫醇螯合物系统的三种金属缀合物。这些铼和锝-99和-99m的缀合物是我们最近描述的双氨基-二硫醇（BAT）缀合物的结构类似物，但是MAMA'螯合物比BAT系统极性更强，因此缀合物的亲脂性要低得多，辛醇-水分配系数低了近80倍。在竞争性结合测定中，Re-和“Tc-MAMA'-孕激素缀合物以大于孕酮本身的亲和力与孕酮受体结合，在直接结合测定中，99mTc-MAMA'缀合物的平衡解离常数 (Kd) 为 0.97 nM。与 11/3 取代孕激素一样，这些缀合物也对孕激素具有显着的结合亲和力。在未成熟雌性大鼠的组织分布研究中，孕激素-99mTc-MAMA'缀合物显示出对主要靶组织（例如子宫）的选择性摄取，而不是血液和非靶组织（例如肌肉）；这些摄取比率分别达到最大水平5和4。孕激素 ORG2058。代谢研究表明，子宫内的放射性在 4 小时内基本未代谢，而肝脏活性完全由代谢物引起。孕激素-" mTc-MAMA' 缀合物的体内行为与标记的 BAT 缀合物相似：其吸收选择性略高于 BAT 缀合物。靶组织摄取较低。可能限制这些缀合物的靶组织摄取特性的因素是它们对黄体酮受体的中等亲和力、它们与糖皮质激素受体的大量结合以及它们的大分子总体尺寸。
We have prepared and evaluated three metal conjugates of a progestin-monoamine-monoamide (MAMA') bisthiol chelate system. These conjugates of rheniumand technetium-99 and-99m, are structural analogs of the bisamino-bisthiol (BAT) conjugates we have described recently, but the MAMA'chelate, being more polar than the BAT system, gives a conjugate that is much less lipophilic, having an octanol-water partition coefficient that is nearly 80-fold lower. In competitive binding assays, the Re-and" Tc-MAMA'-progestin conjugates bind to the progesterone receptor with affinities greater than that of progesterone itself, and in a direct binding assay, the equilibrium dissociation constant (Kd) of the 99mTc-MAMA'conjugate was 0.97 nM. As is typical for 11/3-substituted progestins, these conjugates also have substantial binding affinity for glucocorticoid receptors. In tissue distribution studies in immature female rats, the progestin-99mTc-MAMA'conjugatesshow selective uptake for principal target tissue (such as uterus) over that of blood and nontarget tissue (such as muscle); these uptake ratios reach maximum levels of 5 and 4, respectively. Uptake by fat, liver, and kidney is quite high; however, only the uptake in uterus is displaceable upon coinjection of the selective progestin ORG2058. Metabolism studiesshow that the radioactivity in the uterus is essentially unmetabolized out to 4 h, while liveractivity is completely due to metabolites. Other tissues show an intermediate fraction of unmetabolized conjugates that decreases with time. The invivo behavior of the progestin-" mTc-MAMA'conjugate is similar to that of the labeled BAT conjugate: its uptake selectivity is somewhat greater than that of the BAT conjugate, but its target tissue uptake is lower. Factors that may be responsible for limiting the target tissue uptake properties of these conjugates are their moderate affinity for progesterone receptor, their substantial bindingto glucorticoid receptors, and their large overall molecular size.