Development of Octanuclear Iron Clusters as MRI Contrast Agents

我们希望通过开发用于此目的的新型铁基材料来满足对新型MRI对比度增强剂日益增长的需求。我们将使用一个八核铁氧簇作为基本的顺磁性核心，这将取代在其外围，以实现水溶性，并允许操纵其药代动力学。该项目的目的是提供一个模块拥有所需的质子弛豫性能，以及周边网站服从进一步修改。后者将允许开发可注射的 造影剂的常规合成程序。长期目标是生产一类基于铁氧簇的新型造影剂。 我们将制备顺磁性的八核Fe”"-氧代-吡唑簇的水溶性衍生物Fe/8（Mu/4-O）4（Mu/PZ）12 X 4，pz =吡唑阴离子，X = Cl，Br，以便它们可以被筛选为用于体内和体外MRI应用的潜在对比增强剂。由于建立了这种疏水簇及其一些衍生物的可靠合成，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-取代的吡唑配体从头合成簇，B）通过在吡唑的空间上不受阻碍的4-位上的取代对簇进行后修饰，或在末端卤化物配体处。新的八核簇将通过标准方法进行充分表征，并对其弛豫率、生物活性和成像特性进行评估。

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.