Synthesis and in vivo evaluation of new contrast agents for cardiac MRI
Synthesis and in vivo evaluation of new contrast agents for cardiac MRI
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DOI：
10.1021/jm980454v
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发表时间：
1999-07-29
影响因子：
7.3
通讯作者：
Elgavish, AA
中科院分区：
文献类型：
--
作者：
Saab-Ismail, NH;Simor, T;Elgavish, AA
合成了N-3，N-6-bis(2‘-myristoyloxyethyl)-1，8-dioxotriethylenetetraamine-N，N，N’，N‘-四乙酸二乙酯(1)的类似物2-6，它们也是基于DTTA结构的，但含有较短的脂肪酰基链，以改善相应的Gd配合物的水溶性。1和3-5的Gd络合物在水中的溶解度很低。因此，脂质体制剂对于其在体内MRI的应用是必要的。这些脂质体制剂在体外保持了较高的松弛系数(分别为27.1、21.57、20.32、23.1 S(-1)mm(-1))，并能持续增强磁共振信号强度(单位数分别为67.2、38.4、52.1、41.7)。2的Gd络合物在水中很容易溶解。然而，它在血液中的寿命很短。类似物6，N-(2-丁氧基乙基)-N‘-(2-乙氧基乙基)-N，N’-双[N“，N”-bis(carboxymethyl)acetamido]-1，2-ethanediamine(ABE-DTTA)已显示出作为一种水溶性的心脏特异性磁共振造影剂的潜力。它在浓度为25 mM的水中完全溶解，可用于制备可注射剂量。该络合物的体外弛豫系数为16.24 S(-1)mm(-1)。该制剂在给药后15min内在心脏组织中的特异性蓄积达到最大，导致MRI信号强度持续增强43.6%。这种增强至少持续3小时，因此表明这种造影剂在心肌中有相当长的寿命，不会对心功能参数产生有害影响。
Analogues 2-6 of N-3,N-6-bis(2'-myristoyloxyethyl)-1,8-dioxotriethylenetetraamine-N,N,N',N'-tetraacetic acid (BME-DTTA) (1), which like 1 are also based on the DTTA structure but contain shorter fatty acyl chains, were synthesized to improve the water solubility of the corresponding gadolinium complexes. The gadolinium complexes of 1 and 3-5 have very low solubility in water. Thus liposomal preparations are necessary for their in vivo MRI application. These liposomal preparations retain high in vitro relaxivities (27.1, 21.57, 20.32, 23.1 s(-1) mM(-1), respectively) and induce sustained MRI signal intensity enhancements (67.2, 38.4, 52.1, 41.7 in arbitrary units, respectively). The gadolinium complex of 2 is quite soluble in water. Its lifetime in the blood stream, however, is short. The gadolinium complex of analogue 6, N-(2-butyryloxyethyl)-N'-(2-ethyloxyethyl)-N,N'-bis[N",N"-bis(carboxymethyl)acetamido]-1,2-ethanediamine (ABE-DTTA), has demonstrated its potential as a water-soluble, cardiac specific, MRI contrast agent. It is completely soluble in water at a 25 mM concentration, allowing the preparation of an injectable dose. The in vitro relaxivity of the complex is 16.24 s(-1) mM(-1). The agent shows a specific accumulation in the heart tissue reaching its maximum within 15 min after administration, inducing a sustained MRI signal intensity enhancement of 43.6%. This enhancement lasts far at least 3 h, thus indicating a reasonably long lifetime of this contrast agent in the myocardium without deleterious effects on heart function parameters.