University of Debrecen, Department of Physical Chemistry, Egyetem tér 1, Debrecen H-4032, Hungary.
University of Debrecen, Department of Physical Chemistry, Egyetem tér 1, Debrecen H-4032, Hungary.
J Inorg Biochem. 2020 May;206:111042. doi: 10.1016/j.jinorgbio.2020.111042. Epub 2020 Feb 20.
The 1,7-diacetate-4,10-diacetamide substituted 1,4,7,10-tetraazacyclododecane structural unit is common to several responsive Magnetic Resonance Imaging (MRI) contrast agents (CAs). While some of these complexes (agents capable of sensing fluctuations in Zn, Ca etc. ions) have already been tested in vivo, the detailed physico-chemical characterization of such ligands have not been fully studied. To fill this gap, we synthesized a representative member of this ligand family possessing two acetate and two n-butylacetamide pendant side-arms (DO2A2M = 1,4,7,10-tetraazacyclodoecane-1,7-di(acetic acid)-4,10-di(N-butylacetamide)), and studied its complexation properties with some essential metal and a few lanthanide(III) (Ln(III)) ions. Our studies revealed that the ligand basicity, the stability of metal ion complexes, the trend of stability constants along the Ln(III) series, the formation rates of the Ln(III) complexes and the exchange rate of the bound water molecule in the Gd(III) complex fell between those of Ln(DOTA) and Ln(DOTA-tetra(amide)) complexes (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM = 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane). The only exception is the stability of Cu(DO2A2M) which was found to be only slightly lower than that of Cu(DOTA) (log K = 19.85 vs. 21.98). This is likely reflects exclusive coordination of the negatively charged acetate donor atoms to the Cu ion forming an octahedral complex with the amides remaining uncoordinated. The only anomaly observed during the study was the rates of acid assisted dissociation of the Ln(III) complexes, which occur at a rate similar to those observed for the Ln(DOTA) complexes. These data indicate that even though the Ln(DO2A2M) complexes have lower thermodynamic stabilities, their kinetic inertness should be sufficient for in vivo use.
1,7-二乙酸酯-4,10-二乙酰胺取代的 1,4,7,10-四氮杂环十二烷结构单元是几种响应性磁共振成像（MRI）对比剂（CA）的共同特征。虽然这些配合物中的一些（能够感应 Zn、Ca 等离子波动的试剂）已经在体内进行了测试，但这些配体的详细物理化学特性尚未得到充分研究。为了填补这一空白，我们合成了该配体家族的一个代表性成员，该成员具有两个乙酸酯和两个正丁基乙酰胺侧臂（DO2A2M=1,4,7,10-四氮杂环十二烷-1,7-二（乙酸）-4,10-二（N-正丁基乙酰胺）），并研究了其与一些必需金属和一些镧系（III）（Ln（III））离子的络合性质。我们的研究表明，配体的碱性、金属离子配合物的稳定性、Ln（III）系列中稳定常数的趋势、Ln（III）配合物的形成速率以及 Gd（III）配合物中结合水分子的交换速率介于 Ln（DOTA）和 Ln（DOTA-四（酰胺））配合物之间（DOTA=1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸，DOTAM=1,4,7,10-四（氨基甲酰甲基）-1,4,7,10-四氮杂环十二烷）。唯一的例外是 Cu（DO2A2M）的稳定性，发现其仅略低于 Cu（DOTA）（log K=19.85 对 21.98）。这可能反映了带负电荷的乙酸盐供体原子与 Cu 离子的排他配位，形成具有酰胺未配位的八面体配合物。在研究过程中观察到的唯一异常是 Ln（III）配合物的酸辅助解离速率，其发生速率与观察到的 Ln（DOTA）配合物的速率相似。这些数据表明，尽管 Ln（DO2A2M）配合物的热力学稳定性较低，但它们的动力学惰性应该足以用于体内。
