Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Department of Chemistry, Humboldt-Universität zu Berlin, Berlin, Germany.
Magn Reson Med. 2021 Jun;85(6):3370-3382. doi: 10.1002/mrm.28664. Epub 2021 Feb 4.
Low molecular weight iron(III) complex-based contrast agents (IBCA) including iron(III) trans-cyclohexane diamine tetraacetic acid [Fe(tCDTA)] could serve as alternatives to gadolinium-based contrast agents in MRI. In search for IBCA with enhanced properties, we synthesized derivatives of [Fe(tCDTA)] and compared their contrast effects.
Trans-cyclohexane diamine tetraacetic acid (tCDTA) was chemically modified in 2 steps: first the monoanhydride of Trans-cyclohexane diamine tetraacetic acid was generated, and then it was coupled to amines in the second step. After purification, the chelators were analyzed by high-performance liquid chromatography, mass spectrometry, and NMR spectrometry. The chelators were complexed with iron(III), and the relaxivities of the complexes were measured at 0.94, 1.5, 3, and 7 Tesla. Kinetic stabilities of the complexes were analyzed spectrophotometrically and the redox properties by cyclic voltammetry.
Using ethylenediamine (en) and trans-1,4-diaminocyclohexane, we generated monomers and dimers of tCDTA: en-tCDTA, en-tCDTA-dimer, trans-1,4-diaminocyclohexane-tCDTA, and trans-1,4-diaminocyclohexane-tCDTA-dimer. The iron(III) complexes of these derivatives had similarly high stabilities as [Fe(tCDTA)] . The iron(III) complexes of the trans-1,4-diaminocyclohexane derivatives had higher T relaxivities than [Fe(tCDTA)] that increased with increasing magnetic field strengths and were highest at 6.8 L·mmol ·s per molecule for the dimer. Remarkably, the relaxivity of [Fe(en-tCDTA)] had a threefold increase from neutral pH toward pH6.
Four iron(III) complexes with similar stability in comparison to [Fe(tCDTA)] were synthesized. The relaxivities of trans-1,4-diaminocyclohexane-tCDTA and trans-1,4-diaminocyclohexane-tCDTA-dimer complexes were in the same range as gadolinium-based contrast agents at 3 Tesla. The [Fe(en-tCDTA)] complex is a pH sensor at weakly acidic pH levels, which are typical for various cancer types.
基于低分子量铁（III）配合物的对比剂（IBCA），包括铁（III）反式环已烷二胺四乙酸[Fe（tCDTA）]，可以替代 MRI 中的钆基对比剂。为了寻找具有增强性能的 IBCA，我们合成了[Fe（tCDTA）]的衍生物，并比较了它们的对比效果。
反式环己烷二胺四乙酸（tCDTA）通过两步化学修饰：首先生成反式环己烷二胺四乙酸的单酸酐，然后在第二步与胺偶联。纯化后，通过高效液相色谱、质谱和 NMR 光谱分析螯合剂。螯合剂与铁（III）配位，在 0.94、1.5、3 和 7 特斯拉下测量复合物的弛豫率。通过分光光度法分析复合物的动力学稳定性，并通过循环伏安法分析其氧化还原性质。
使用乙二胺（en）和反式-1,4-二氨基环己烷，我们生成了 tCDTA 的单体和二聚体：en-tCDTA、en-tCDTA 二聚体、反式-1,4-二氨基环己烷-tCDTA 和反式-1,4-二氨基环己烷-tCDTA 二聚体。这些衍生物的铁（III）配合物与[Fe（tCDTA）]一样稳定。反式-1,4-二氨基环己烷衍生物的铁（III）配合物的 T 弛豫率高于[Fe（tCDTA）]，随着磁场强度的增加而增加，在二聚体时最高可达 6.8 L·mmol·s 每分子。值得注意的是，[Fe（en-tCDTA）]的弛豫率在从中性 pH 向 pH6 时增加了三倍。
与[Fe（tCDTA）]相比，合成了四种具有相似稳定性的铁（III）配合物。在 3 特斯拉时，反式-1,4-二氨基环己烷-tCDTA 和反式-1,4-二氨基环己烷-tCDTA 二聚体的弛豫率与钆基对比剂相当。[Fe（en-tCDTA）]配合物是一种在弱酸性 pH 值下的 pH 传感器，这种 pH 值在各种癌症类型中很常见。
