Towards extracellular Ca2+ sensing by MRI: synthesis and calcium-dependent 1H and 17O relaxation studies of two novel bismacrocyclic Gd3+ complexes.
Towards extracellular Ca2+ sensing by MRI: synthesis and calcium-dependent 1H and 17O relaxation studies of two novel bismacrocyclic Gd3+ complexes.
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DOI：
10.1007/s00775-007-0296-9
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发表时间：
2008-01
影响因子：
3
通讯作者：
Toth, Eva
中科院分区：
文献类型：
--
作者：
Dhingra, Kirti;Fouskova, Petra;Angelovski, Goran;Maier, Martin E.;Logothetis, Nikos K.;Toth, Eva
两种新的双大环Gd3+螯合物含有特定的Ca2+结合位点，作为潜在的MRI造影剂，用于检测细胞外空间毫摩尔水平的Ca2+浓度变化。在配体中，Ca2+敏感的bapta -双酰胺中心部分通过乙烯（L1）或丙烯（L2）单元与DO3A大环分离[H4BAPTA是1,2-二（邻氨基苯氧基）乙烷-N，N,N ',N ' -四乙酸；H3DO3A是1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸]。用1H弛豫滴定法研究了Gd3+配合物对Ca2+和Mg2+的敏感性。当Ca2+与Gd2L1和Gd2L2结合时，最大弛豫度分别增加了15%和10%，与Mg2+相比，Gd2L1对Ca2+具有明显的选择性。对于Ca2+结合，通过松弛法测定了log K = 1.9 （Gd2L1）和log K = 2.7 （Gd2L2）的结合常数。对相应的Eu3+类似物进行了发光寿命测定和紫外-可见分光光度测定，证明配合物以一水合和非水合形式存在；Ca2+结合在配体的中心部分诱导形成一水合状态。Ca2+的加入导致了弛豫度的增加。在Ca2+存在和不存在的情况下，对Gd2L1进行了1H核磁弛豫色散和17O NMR研究，以评估影响弛豫度的微观参数。在Ca2+结合时，水交换略有加速，这可能与中心部分的空间需求增加导致ln -水结合相互作用的不稳定有关。本文的在线版本（doi:10.1007/s00775-007-0296-9）包含补充材料，可供授权用户使用。
Two new bismacrocyclic Gd3+ chelates containing a specific Ca2+ binding site were synthesized as potential MRI contrast agents for the detection of Ca2+ concentration changes at the millimolar level in the extracellular space. In the ligands, the Ca2+-sensitive BAPTA-bisamide central part is separated from the DO3A macrocycles either by an ethylene (L1) or by a propylene (L2) unit [H4BAPTA is 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; H3DO3A is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid]. The sensitivity of the Gd3+ complexes towards Ca2+ and Mg2+ was studied by 1H relaxometric titrations. A maximum relaxivity increase of 15 and 10% was observed upon Ca2+ binding to Gd2L1 and Gd2L2, respectively, with a distinct selectivity of Gd2L1 towards Ca2+ compared with Mg2+. For Ca2+ binding, association constants of log K = 1.9 (Gd2L1) and log K = 2.7 (Gd2L2) were determined by relaxometry. Luminescence lifetime measurements and UV–vis spectrophotometry on the corresponding Eu3+ analogues proved that the complexes exist in the form of monohydrated and nonhydrated species; Ca2+ binding in the central part of the ligand induces the formation of the monohydrated state. The increasing hydration number accounts for the relaxivity increase observed on Ca2+ addition. A 1H nuclear magnetic relaxation dispersion and 17O NMR study on Gd2L1 in the absence and in the presence of Ca2+ was performed to assess the microscopic parameters influencing relaxivity. On Ca2+ binding, the water exchange is slightly accelerated, which is likely related to the increased steric demand of the central part leading to a destabilization of the Ln–water binding interaction. The online version of this article (doi:10.1007/s00775-007-0296-9) contains supplementary material, which is available to authorized users.
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