Dhingra Kirti, Fousková Petra, Angelovski Goran, Maier Martin E, Logothetis Nikos K, Tóth Eva
Max Planck Institute for Biological Cybernetics, Tübingen, Germany.
J Biol Inorg Chem. 2008 Jan;13(1):35-46. doi: 10.1007/s00775-007-0296-9. Epub 2007 Sep 15.
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 (1)H 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.
合成了两种含有特定Ca²⁺结合位点的新型双大环Gd³⁺螯合物，作为潜在的磁共振成像（MRI）造影剂，用于检测细胞外空间中毫摩尔水平的Ca²⁺浓度变化。在这些配体中，对Ca²⁺敏感的BAPTA-双酰胺中心部分通过一个乙烯基（L1）或一个丙烯基（L2）单元与DO3A大环分离[H4BAPTA为1,2-双（邻氨基苯氧基）乙烷-N,N,N',N'-四乙酸；H3DO3A为1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸]。通过¹H弛豫滴定研究了Gd³⁺配合物对Ca²⁺和Mg²⁺的敏感性。Ca²⁺与Gd2L1和Gd2L2结合时，观察到弛豫率分别最大增加15%和10%，与Mg²⁺相比，Gd2L1对Ca²⁺具有明显的选择性。通过弛豫测定法确定Ca²⁺结合的缔合常数为log K = 1.9（Gd2L1）和log K = 2.7（Gd2L2）。对相应Eu³⁺类似物的发光寿命测量和紫外-可见分光光度法证明，配合物以一水合物和非水合物形式存在；配体中心部分的Ca²⁺结合诱导了一水合物状态的形成。水合数的增加解释了添加Ca²⁺时观察到的弛豫率增加。对不存在和存在Ca²⁺时的Gd2L1进行了¹H核磁共振弛豫分散和¹⁷O NMR研究，以评估影响弛豫率的微观参数。Ca²⁺结合时，水交换略有加速，这可能与中心部分空间需求增加导致Ln-水结合相互作用不稳定有关。
