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

该STTRI期项目将开发铁配位络合物，作为目前用于临床核磁共振诊断检查的Gd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)试剂的人群。这包括患有肾脏疾病的患者和那些经常进行MRI扫描并可能积聚Gd(III)的患者。这项拟议的研究涉及在S大学联合实验室最初研究的基础上，对新的三价铁配位络合物的研究。将制备新的铁络合物作为造影剂，并在活体小鼠身上进行研究，以改善造影剂的特性，如从体内清除。对铁络合物的基础研究将增加有关铁的顺磁性的知识。对于最有希望的铁(III)造影剂，其合成方法将适用于大规模制备和纯度测定。铁核磁共振造影剂也可能对社会有益，因为它减少了供水中的Gd。此外，铁作为一种丰富的元素，在美国比Gd更便宜，更容易获得。铁核磁共振造影剂的商业化将在化学制造、销售和与健康相关的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在活体小鼠中都能产生与临床使用的4.7特斯拉Gd(III)络合物相媲美的水质子的纵向(T1)弛豫度。重要的是，这些络合物含有大环配体，可以稳定铁的三价状态(氧化还原电位为负)，即使在抗坏血酸作为还原剂和过氧化氢存在的情况下也不产生活性氧物种。通过改变大环配体上与Fe(III)结合的配位侧基来研究外层水和内层水相互作用的重要性。辅助基团将改变，以增加与血清蛋白的结合，并修改造影剂通过肾脏或肝胆途径的清除途径。在生物相关的条件下，络合物将对释放铁的动力学惰性进行优化。将对每一种新的复合体进行细胞培养毒性研究。这项研究将集中在用于Fe(III)络合物体外研究的中试制备，以及更大规模的制备和最有前途的新衍生物的高效液相分析。在4.7T扫描仪上进行的小鼠体内MRI扫描将被用来跟踪铁造影剂的分布和清除随时间的变化。

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.