Imidazole-Appended Macrocyclic Complexes of Fe(II), Co(II), and Ni(II) as ParaCEST Agents

The solution chemistry
and solid state structures of the Co­(II), Fe­(II), and Ni­(II) complexes
of N,N′-bis­(imidazole-2-ylmethyl)-4,10-diaza-15-crown-5
(HINO) are reported. The Co­(II) and Ni­(II) complexes
of HINO are the first examples of paraCEST agents (paramagnetic
chemical exchange saturation transfer) that feature exchangeable imidazole
NH protons. The crystal structures of [Co­(HINO)]­CoCl4·H2O and [Fe­(HINO)]­(CF3SO3)2 have the metal ions coordinated
to four nitrogen and three oxygen donor atoms of the macrocyclic ligand
in a distorted pentagonal bipyramidal geometry. In [Ni­(HINO)]­(CF3SO3)2, the nickel ion
is bound to only two of the three ether oxygens and three nitrogens
to produce a complex with a distorted octahedral geometry. The 1H NMR spectra of the three paramagnetic complexes show resonances
characteristic of effective C2 symmetry
in solution. CEST peaks attributed to the imidazole NH proton of the
pendent group are observed at 32 and 55 ppm away from bulk water for
[Co­(HINO)]2+ and [Ni­(HINO)]2+, respectively, on a 11.7 or 9.4 T NMR spectrometer. For
both complexes, an optimal CEST effect was observed at pH 7.2, and
the rate constant for proton exchange under these conditions was 1.0
× 103 s–1. [Fe­(HINO)]2+ did not produce a CEST peak due to oxidation of the
complex in water at neutral pH. The CEST peak of [Co­(HINO)]2+ or [Ni­(HINO)]2+ is observed
in the presence of human serum albumin (HSA). These complexes show
enhanced kinetic inertness toward dissociation in acid or in the presence
of HSA in comparison to analogous complexes with amide pendent groups.

本文报道了配体N,N′-二(咪唑-2-甲基)-4,10-二氮杂-15-冠-5（HINO）与二价钴（Co(II)）、二价铁（Fe(II)）及二价镍（Ni(II)）形成配合物的溶液化学与固态结构。其中HINO与Co(II)、Ni(II)形成的配合物为首批具备可交换咪唑NH质子特征的顺磁化学交换饱和转移（paramagnetic chemical exchange saturation transfer, paraCEST）造影剂。[Co(HINO)]CoCl₄·H₂O与[Fe(HINO)](CF₃SO₃)₂的晶体结构显示，金属离子与大环配体的4个氮原子及3个氧配位原子结合，形成畸变五角双锥配位构型。而在[Ni(HINO)](CF₃SO₃)₂中，镍离子仅与3个氮原子及2个醚氧原子配位，构成畸变八面体构型。三种顺磁配合物的氢核磁共振（¹H NMR）谱均呈现出符合溶液中有效C₂对称的共振特征。在11.7 T或9.4 T核磁共振波谱仪上，[Co(HINO)]²⁺与[Ni(HINO)]²⁺的侧链咪唑NH质子对应的CEST峰分别位于距体相水32 ppm与55 ppm处。两种配合物的最佳CEST效应均在pH 7.2条件下测得，该条件下的质子交换速率常数为1.0×10³ s⁻¹。[Fe(HINO)]²⁺因在中性pH水溶液中发生氧化反应，未观测到CEST峰。在人血清白蛋白（human serum albumin, HSA）存在的条件下，仍可检测到[Co(HINO)]²⁺或[Ni(HINO)]²⁺的CEST峰。相较于带有酰胺侧基的同类配合物，本研究中的配合物在酸性环境或人血清白蛋白存在时，展现出更优异的抗解离动力学惰性。