Octanuclear Iron Clusters as MRI Contrast Agents

我们希望通过开发一类新的铁基材料来满足对新的MRI对比剂日益增长的需求。我们将使用一个八核铁氧簇作为基本的顺磁核心，它将被取代在其外围，以实现水溶性和允许操纵其药代动力学。该项目的目的是提供一种具有所需的质子弛豫特性以及可进一步修改的外围位置的模块。后者将允许开发可注射的 造影剂通过常规的合成程序。长期目标是生产一类基于铁氧簇合物的新型造影剂。 我们将制备一个顺磁性的八核Fe“”-氧代-吡唑烷基团簇，Fe/8(Mu/4-O)4(Mu/Pz)12X4，PZ=吡唑烷阴离子，X=CI，Br.的水溶性衍生物，这样它们就可以作为体内和体外MRI应用的潜在造影剂。由于已建立了该疏水簇合物及其少数衍生物的可靠合成方法，我们将通过两种方法在其外围引入亲水基团来制备其水溶性衍生物：a)使用4-取代吡唑配体从头合成簇合物，b)通过在吡唑的4位立体无阻碍位置或在末端卤化物配体上进行取代来修饰簇合物。新的八核簇合物将用标准方法进行充分的表征，并将评估它们的弛豫性能、生物活性和成像性能。

We wish to address the growing demand for new MRI contrast-enhancing agents by developing a new class of iron-based materials for this purpose. We will use an octanuclear iron-oxo cluster as the basic paramagnetic core, which will be substituted at its periphery in order to achieve water-solubility and permit manipulation of its pharmacokinetics. The aim of this project is to deliver a module possessing the desired proton-relaxivity properties, as well as peripheral sites amenable to further modification. The latter will permit the development of injectable contrast agents by routine synthetic procedures. The long-term goal is to produce a new class of contrast agents based on iron-oxo cluster. We will prepare water-soluble derivatives of a paramagnetic, octanuclear Fe""-oxo-pyrazolato cluster, Fe/8(Mu/4-O)4(Mu/PZ) 12X4, pz = pyrazolato anion, X = CI, Br, so that they can be screened as potential contrast enhancing agents for in vivo and in vitro MRI applications. As a reliable synthesis of this hydrophobic cluster, as well as a few of its derivatives, is established, we will approach the preparation of its water-soluble derivatives by introducing hydrophilic groups at its periphery by two methods: a) De novo cluster synthesis using 4-substituted pyrazole ligands, b) post-modification of the cluster by substitution at the stericaly unhindered 4-position of the pyrazoles, or at the terminal halide ligands. The new octanuclear clusters will be fully characterized by standard methods, and their relaxivities, biological activities and imaging properties will be evaluated.