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

这项小型企业技术转移（STTR）二期项目的更广泛/商业影响将集中在制备新的铁基化合物，作为更安全的磁共振成像（MRI）造影剂，这一问题尤其影响频繁进行MRI扫描的患者和慢性肾脏疾病患者。该项目将推动更安全的医学成像的发展。STTR二期项目将专注于进一步开发第一种基于Fe（III）大环的T1 MRI造影剂，作为Gd（III）造影剂的替代品。这些配合物中的大环配体用于控制铁的自旋和氧化状态，以及药物的生物分布和药代动力学清除。大环配体将被修饰以进一步提高Fe（III）配合物的T1弛豫度。配合物的亲水性将增加，以更好地模拟基于Gd（III）的药物的清除概况。扩大合成程序将产生足够的化合物批次，用于小鼠毒性研究，包括最大耐受剂量（MTD）和无不良反应水平（NOAEL），大鼠成像研究以及组织学和代谢小组。最有希望的复合物将进行进一步的毒性研究，包括Ames测试、胸苷激酶细胞筛选和心脏毒性分析。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader/commercial impact of this Small Business Technology Transfer (STTR) Phase II project will focus on the preparation of new iron-based compounds as safer contrast agents for magnetic resonance imaging (MRI), an issue that particularly affects patients who have frequent MRI scans and those with chronic kidney disease. This project will advance the development of safer medical imaging.This STTR Phase II project will focus on further development of the first Fe(III) macrocycle-based T1 MRI contrast agents as alternatives to Gd(III) agents. The macrocyclic ligands in these complexes are used to control the spin and oxidation state of the iron, as well as the biodistribution and pharmacokinetic clearance of the agent. The macrocyclic ligands will be modified to further increase T1 relaxivity of the Fe(III) complexes. The hydrophicility of the complexes will be increased to better mimic the clearance profiles of Gd(III) based agents. Scale-up of the synthetic procedures will produce sufficient compound batches for toxicity studies in mice, including the maximum tolerated dose (MTD) and the no adverse effect level (NOAEL), imaging studies in rats, as well as histology and metabolic panels. The most promising complexes will be subjected to further toxicity studies including Ames testing, thymidine kinase cell screens and cardiotoxicity assays.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.