STTR Phase I: Relaxivity mechanisms of Fe(III) MRI contrast agents

该STTR I期项目将开发铁配位络合物，作为目前用于临床MRI诊断检查的钆造影剂的替代品。 需要新的MRI造影剂来服务于不能耐受Gd（III）药物的人群。 这包括患有肾脏疾病的患者和那些经常进行MRI扫描并可能积累Gd（III）的患者。 拟议的研究涉及新的三价铁配位络合物的基础上，最初研究的共同PI？大学实验室。将制备新的铁络合物，并在活小鼠中作为造影剂进行研究，以改善药剂的特性，例如从体内清除。 铁配合物的基础研究将为铁的顺磁性质提供更多的知识，对于最有前途的铁（III）造影剂，其合成方法将适合于大规模制备和纯度测定。 铁MRI造影剂也可能通过减少供水中的钆而有益于社会。 此外，铁作为一种丰富的元素，在美国比钆便宜且更容易获得。铁MRI造影剂的商业化将在化学制造、销售和健康相关职业中创造就业机会。该项目所基于的铅Fe（III）配位络合物在体外条件下和活小鼠中产生的水质子的纵向（T1）弛豫率可与临床使用的Gd（III）络合物在4.7特斯拉下相媲美。重要的是，这些络合物含有大环配体，其稳定三价态的铁（相对于NHE的负氧化还原电位），并且即使在抗坏血酸盐作为还原剂和过氧化物的存在下也不产生活性氧物质。 外层水和内层水相互作用的重要性将通过改变大环配体上的配位侧基与Fe（III）结合来研究。 将改变辅助组，以增加与血清蛋白的结合，并改变造影剂通过肾脏或肝胆途径的清除途径。 将针对在生物学相关条件下释放铁的动力学惰性对复合物进行优化。 将对每种新复合物进行细胞培养毒性研究。这项研究将集中在两个试点规模的制备研究的Fe（III）配合物在体外，也对较大规模的制剂和HPLC分析最有前途的新衍生物。 在4.7 T扫描仪上对小鼠进行体内MRI扫描，以跟踪铁造影剂随时间的分布和清除。

This STTR Phase I project will undertake the development of iron coordination complexes as alternatives for gadolinium contrast agents which are currently used in clinical MRI diagnostic exams. New MRI contrast agents are needed to serve the segment of the population who cannot tolerate Gd(III) agents. This includes patients with kidney disease and those who have frequent MRI scans and may accumulate Gd(III). The proposed research involves the study of new trivalent iron coordination complexes based on those initially studied in the co-PI?s university laboratory. New iron complexes will be prepared and studied as contrast agents in live mice to improve characteristics of the agents such as clearance from the body. Fundamental studies of the iron complexes will add to the body of knowledge on the paramagnetic properties of iron.For the most promising Fe(III) contrast agents, the synthetic procedures will be adapted for large scale preparation and purity determination. Iron MRI contrast agents may also be beneficial to society by reducing gadolinium in water supply. Furthermore, iron as an abundant element is less expensive and more readily available in the USA than is gadolinium. The commercialization of iron MRI contrast agents will create jobs in chemical manufacturing, sales, and in health-related occupations.The lead Fe(III) coordination complex on which this project is based produces longitudinal (T1) relaxivity of water protons that rival clinically used Gd(III) complexes at 4.7 Tesla, both under in vitro conditions and also in live mice. Importantly, these complexes contain macrocyclic ligands that stabilize iron in the trivalent state (negative redox potentials versus NHE) and do not produce reactive oxygen species even in the presence of ascorbate as a reductant and peroxide. The importance of outersphere water and innersphere water interactions will be studied by varying the coordinating pendent groups on the macrocyclic ligand which is bound to Fe(III). The ancillary group will be varied to increase binding to serum proteins and to modify the clearance route of the contrast agents either through kidneys or through hepatobiliary routes. The complexes will be optimized for kinetic inertness towards release of iron under biologically relevant conditions. Toxicity studies in cell culture will be carried out on each of the new complexes. This research will focus on both pilot scale preparation for the study of the Fe(III) complexes in vitro and also on larger scale preparations and HPLC analysis of the most promising new derivatives. In vivo MRI scans in mice on a 4.7 T scanner will be used to track the distribution and clearance of the iron contrast agents as a function of time.