Betebenner D A, Carney P L, Zimmer A M, Kazikiewicz J M, Brücher E, Sherry A D, Johnson D K
Abbott Laboratories, Department 90M, Abbott Park, Illinois 60064.
Bioconjug Chem. 1991 Mar-Apr;2(2):117-23. doi: 10.1021/bc00008a007.
A conjugate in which the steroid nucleus of cholic acid was linked to EDTA via an 11-atom spacer was obtained by reacting the succinimidyl ester of cholic acid with the amine formed by reaction of a benzyl isothiocyanate derivative of EDTA with N-(tert-butoxycarbonyl)ethylenediamine and subsequent deprotection. Potentiometric titration studies with model complexes showed that the EDTA moiety retained the ability to form 1:1 chelates of high thermodynamic stability, although formation constants were some 3-4 log K units lower for complexes of the conjugate than for the analogous chelates with underivatized EDTA. A complex formed between the cholic acid-EDTA conjugate and 111InIII was clearly rapidly into the liver when injected iv into mice, with subsequent excretion from the liver into the gastrointestinal tract being complete within 1 h of injection. Radioscintigraphic imaging studies conducted in a rabbit given the 111In-labeled conjugate also showed early liver uptake followed by rapid clearance from the liver into the intestine, with good visualization of the gallbladder in images obtained at 20-25 min postinjection. It is concluded that conjugation to cholic acid provides a useful means for the hepatobiliary delivery of EDTA chelates that otherwise exhibit predominantly extracellular distribution and renal clearance.
通过使胆酸的琥珀酰亚胺酯与由乙二胺四乙酸（EDTA）的苄基异硫氰酸酯衍生物与N-（叔丁氧羰基）乙二胺反应形成的胺反应，并随后进行脱保护，得到了一种共轭物，其中胆酸的甾体核通过一个11原子的间隔基与EDTA相连。对模型配合物的电位滴定研究表明，EDTA部分保留了形成具有高热力学稳定性的1:1螯合物的能力，尽管共轭物配合物的形成常数比与未衍生化的EDTA形成的类似螯合物低约3 - 4个log K单位。当将胆酸-EDTA共轭物与铟-111（InIII）形成的配合物静脉注射到小鼠体内时，它显然迅速进入肝脏，随后在注射后1小时内从肝脏完全排泄到胃肠道。对给予铟-111标记的共轭物的兔子进行的放射性闪烁成像研究也显示，早期肝脏摄取，随后迅速从肝脏清除到肠道，在注射后20 - 25分钟获得的图像中胆囊清晰可见。结论是，与胆酸共轭为乙二胺四乙酸螯合物的肝胆递送提供了一种有用的方法，否则这些螯合物主要表现为细胞外分布和经肾清除。
