The effect of a phosphodiester linking group on albumin binding, blood half-life, and relaxivity of intravascular diethylenetriaminepentaacetato aquo gadolinium(III) MRI contrast agents
The effect of a phosphodiester linking group on albumin binding, blood half-life, and relaxivity of intravascular diethylenetriaminepentaacetato aquo gadolinium(III) MRI contrast agents
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DOI：
10.1021/jm0102351
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发表时间：
2002-08-01
影响因子：
7.3
通讯作者：
Lauffer, RB
中科院分区：
文献类型：
--
作者：
McMurry, TJ;Parmelee, DJ;Lauffer, RB
两亲性钆。研究了配合物作为磁共振成像造影剂的潜力。为了研究亲水性磷酸二酯基团对大鼠白蛋白结合、松弛性和血液半衰期的影响，合成了一系列配合物。因此，合成了具有辛基取代基的二乙烯三胺五乙酸氨基钆（III） （Gd-DTPA）衍生物11a，并将其与类似的辛基衍生物5b进行了比较，5b在钆螯合物和烷基链之间含有磷酸二酯键。同样，将萘基Gd-DTPA衍生物11b与萘基磷酸二酯衍生物5c进行了比较。不能对4,4-二苯基环己基磷酸二酯Gd-DTPA衍生物5a进行直接比较；然而，其药代动力学性质与其他磷酸二酯衍生物相似。虽然磷酸二酯片段的引入使logp降低了约1.7个单位，但在4.5%的人血清白蛋白（HSA）中获得的结合数据表明，含有磷酸二酯基团的衍生物比它们的烷基类似物具有更高的白蛋白亲和力（5b和11a分别为54 +/- 5和44 +/- 4%；5c和11b分别为40 +/- 4和30 +/- 3%）。与单独在磷酸盐缓冲盐水（PBS）中测量的弛豫值(r1 = 4.6-6.6 mM（-1) s(-1)， 20 MHz和37℃）相比，这两类药物在4.5% HSA存在下的弛豫值都增强了(r1 = 16-42 mM（-1) s(-1)）。药代动力学数据表明，化合物5b在大鼠体内的半衰期为14.3 +/- 1.8 min，而非磷酸二酯类似物11a的半衰期为6.20 +/- 0.04 min。同样，磷酸二酯5c的半衰期为14.3 1.7 min，而磷酸二酯11b的半衰期为6.80±0.03 min。与非磷酸二酯类似物相比，磷酸二酯类化合物的胆排泄率显著降低（5b和11a分别为17.7 +/- 4.0和66.9 +/- 3.4%；5c和11b分别为17.0 +/- 1.6和64.3 +/- 9.0%）。大鼠胆道排出率（15.8 +/- 4.4%）和血浆半衰期（23.1 +/- 2.9 min）与其他磷酸二酯衍生物延长的血浆半衰期一致。综上所述，磷酸二酯衍生物的弛豫增强和血液半衰期延长支持了利用内源性白蛋白结合来实现小分子磁共振成像（MRI）造影剂血池样特性的概念。
Amphiphilic gadolinium. complexes were investigated as potential magnetic resonance imaging (MRI) contrast agents. A series of complexes was synthesized in order to study the effect of hydrophilic phosphodiester groups on albumin binding, relaxivity, and blood half-life in rats. Thus, compound 11a, a diethylenetriaminepentaacetato aquo gadolinium(III), (Gd-DTPA) derivative with an octyl substituent, was synthesized and compared to 5b, the analogous octyl derivative containing a phosphodiester linkage between the gadolinium chelate and the alkyl chain. Likewise, 11b, a naphthyl Gd-DTPA derivative, was compared to the naphthyl phosphodiester derivative 5c. A direct comparison is not available for 5a, a 4,4-diphenylcyclohexyl phosphodiester Gd-DTPA derivative; however, its pharmacokinetic properties mirror those of the other phosphodiester derivatives. Although the introduction of the phosphodiester moiety decreased log P by approximately 1.7 units, albumin,binding data obtained in 4.5% human serum albumin (HSA) indicated that derivatives containing the phosphodiester group exhibited somewhat higher albumin affinity than their alkyl analogues (54 +/- 5 and 44 +/- 4% for 5b and 11a, respectively; 40 +/- 4 and 30 +/- 3% for 5c and 11b, respectively). Both classes of agents were characterized by enhanced relaxivity in the presence of 4.5% HSA (r1 = 16-42 mM(-1) s(-1) at 20 MHz and 37 degreesC) as compared with the relaxivity values measured in phosphate-buffered saline (PBS) alone (r1 = 4.6-6.6 mM(-1) s(-1) at 20 MHz and 37 degreesC). Pharmacokinetic data indicated that compound 5b had a half-life of 14.3 +/- 1.8 min in the rat as compared with a half-life of 6.20 +/- 0.04 min for the non-phosphodiester analogue 11a. Similarly, the half-life obtained for the phosphodiester 5c was 14.3 1.7 min as compared with a half-life of 6.80 +/- 0.03 min for, 11b. The percent biliary excretion was significantly lower for the phosphodiester compounds than for non-phosphodiester analogues (17.7 +/- 4.0 and 66.9 +/- 3.4% for 5b and 11a, respectively; 17.0 +/- 1.6 and 64.3 +/- 9.0% for 5c and 11b, respectively). The percent biliary excretion (15.8 +/- 4.4%) and plasma half-life in the rat (23.1 +/- 2.9 min) for 5a are consistent with the extended plasma half-life of the other phosphodiester derivatives. Taken together, the enhanced relaxivity, and extended blood half-life of the phosphodiester derivatives support the concept of using endogenous albumin binding to achieve blood pool-like properties for small-molecule magnetic resonance imaging (MRI) contrast agents.