Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups
Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups
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DOI：
10.3390/molecules25102291
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发表时间：
2020-05-01
期刊：
影响因子：
4.6
通讯作者：
Morrow, Janet R.
中科院分区：
文献类型：
--
作者：
Asik, Didar;Smolinski, Rachel;Morrow, Janet R.
铁(III)络合物含有一个三氮杂环己烷(TACN)大环、两个侧链羟基和第三个辅助侧链，显示出作为MRI造影剂的前景。辅助基团在调节Fe(III)络合物的溶液弛豫度方面起着重要作用，并导致小鼠MRI对比度增强的巨大变化。比较了两个新的Fe(III)配合物，一个含有第三配位羟丙基侧基Fe(L2)，另一个含有阴离子非配位磺酸基Fe(L1)(OH2)。这两个配合物在中性pH下都有一个去质子化的羟基，电极电位代表一个稳定的三价铁中心。在4.7T，37℃的缓冲溶液中，Fe(L1)(OH2)络合物的r(1)弛豫度是饱和络合物Fe(L2)的两倍。变温O-17-核磁共振实验表明，在此条件下，Fe(L1)(OH2)的内球水不能与主体水快速交换。与Fe(L2)相比，Fe(L1)(OH2)中的侧链磺酸基赋予了络合物更高的溶解度。两种化合物的动态核磁共振研究显示，与含有苄基辅助基团的类似物相比，它们的药代动力学清除率有很大差异。快速的血液清除和与血清白蛋白的较差结合使Fe(L1)(OH2)成为一种细胞外液造影剂。
Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH2), are compared. Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r(1) relaxivity of the Fe(L1)(OH2) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 degrees C in buffered solutions. However, variable-temperature O-17-NMR experiments show that the inner-sphere water of Fe(L1)(OH2) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH2) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH2) for development as an extracellular fluid contrast agent.