Payne Katherine M, Woods Mark
Department of Chemistry, Portland State University , 1719 SW 10th Avenue, Portland, Oregon 97201, United States.
Bioconjug Chem. 2015 Feb 18;26(2):338-44. doi: 10.1021/bc500593h. Epub 2015 Jan 30.
The bifunctional chelator IB-DOTA has found use in a range of biomedical applications given its ability to chelate many metal ions, but in particular the lanthanide(III) ions. Gd(3+) in particular is of interest in the development of new molecular imaging agents for MRI and is highly suitable for chelation by IB-DOTA. Given the long-term instability of the aryl isothiocyanate functional group we have used the more stable nitro derivative (NB-DOTA) to conduct a follow-up study of some of our previous work on the coordination chemistry of chelates of these BFCs. Using a combination of NMR and HPLC to study the Eu(3+) and Yb(3+) chelates of NB-DOTA, we have demonstrated that this ligand will produce two discrete regioisomeric chelates at the point at which the metal ion is introduced into the BFC. These regioisomers are defined by the position of the benzylic substituent on the macrocyclic ring: adopting an equatorial position either at the corner or the side of the [3333] ring conformation. These regioisomers are incapable of interconversion and are distinct, separate structures with different SAP/TSAP ratios. The side isomer exhibits an increased population of the TSAP isomer, pointing to more rapid water exchange kinetics in this regioisomer. This has potential ramifications for the use of these two regioisomers of Gd(3+)-BFC chelates in MRI applications. We have also found that, remarkably, there is little or no freedom of rotation about the first single bond extending from the macrocyclic ring to the benzylic substituent. Since this is the linkage through which the chelate is conjugated to the remainder of the molecular imaging probe, this result implies that there may be reduced local rotation of the Gd(3+) chelate within a molecular imaging probe. This implies that this type of BFC could exhibit higher relaxivities than other types of BFC.
双功能螯合剂IB-DOTA因其能够螯合多种金属离子，特别是镧系(III)离子，已在一系列生物医学应用中得到应用。特别是Gd(3+)在新型MRI分子成像剂的开发中备受关注，并且非常适合被IB-DOTA螯合。鉴于芳基异硫氰酸酯官能团的长期不稳定性，我们使用了更稳定的硝基衍生物(NB-DOTA)对我们之前关于这些双功能螯合剂螯合物配位化学的一些工作进行后续研究。通过结合使用NMR和HPLC研究NB-DOTA的Eu(3+)和Yb(3+)螯合物，我们证明该配体在金属离子引入双功能螯合剂的位点会产生两种离散的区域异构体螯合物。这些区域异构体由大环上苄基取代基的位置定义：在[3333]环构象的角或边上采用赤道位置。这些区域异构体不能相互转化，是具有不同SAP/TSAP比率的独特、独立的结构。边侧异构体表现出TSAP异构体的数量增加，表明该区域异构体中的水交换动力学更快。这对于在MRI应用中使用这两种Gd(3+)-双功能螯合剂的区域异构体具有潜在影响。我们还发现，值得注意的是，从大环延伸到苄基取代基的第一个单键几乎没有或没有旋转自由度。由于这是螯合物与分子成像探针其余部分共轭的连接键，这一结果意味着分子成像探针内Gd(3+)螯合物的局部旋转可能会减少。这意味着这种类型的双功能螯合剂可能比其他类型的双功能螯合剂表现出更高的弛豫率。
