Novel Ternary Ligand 99m Tc-Nitrido Complexes as Heart Imaging Agents

描述（由申请人提供）：缺血相关疾病占全球死亡的大多数。心肌缺血是一种严重的疾病，缺血组织的再灌注延迟可能危及生命。在老年人中尤其如此。因此，快速和准确的心肌缺血的早期检测是非常需要的，以便在不可逆的心肌损伤发生之前可以给予各种治疗方案。本项目涉及新型阳离子99 mTc-氮配合物作为新型心脏显像剂的应用。在本项目中将制备和评价的新型99 mTc放射性药物基于我们初步研究的非常有希望的结果，这些结果清楚地表明我们能够产生和评价新型99 mTc放射性示踪剂。这些阳离子99 mTc-硝基配合物的设计方式，其心脏摄取和药代动力学可以通过选择的双齿螯合剂和双膦共配体进行优化。该项目的目标是获得足够的生物分布数据，以便成功提交未来的NIH R 01资助申请。因此，具体目标是：具体目标#1。新型阳离子~（99）mTc-硝基配合物的合成与表征：双齿螯合剂和双膦对阳离子~（99）mTc-硝基配合物亲脂性的影响。具体目标#2阳离子99 mTc-硝基配合物在Sprague-Dawley大鼠体内的生物分布研究：双齿螯合剂和双膦对其生物分布特性和排泄模式的影响。这些研究的结果将使我们能够选择几种有前途的药物在豚鼠模型中进行进一步的生物学评价。具体目标#3阳离子99 mTc-硝基配合物在哈雷豚鼠体内的生物分布研究：进一步证明其用于心肌灌注成像的实用性。如果它们在大鼠和豚鼠模型中显示出高心脏摄取和有利的动力学，则它们更可能在人类中显示出高心脏摄取。一旦我们能够实现这个项目的目标，我们将进行更多的构效关系研究，评估所选择的阳离子99 mTc-亚硝基配合物在疾病动物模型中的作用，并证明放射性示踪剂的流动依赖性和线性。显示这些区域差异的诊断图像在识别灌注不良区域方面非常有用。更好的99 mTc灌注显像剂的识别和成功开发将对缺血相关心脏病（如冠状动脉疾病（CAD））患者的诊断评估和治疗决策产生深远影响。

DESCRIPTION (provided by applicant): Ischemia-related diseases account for the majority of death worldwide. Myocardial ischemia is a serious condition and the delay in reperfusion of ischemic tissues can be life threatening. This is particularly true in the aged population. Thus, rapid and accurate early detection of myocardial ischemia is highly desirable so that various therapeutic regiments can be given before irreversible myocardial damage occurs. This project is related to the use of novel cationic 99mTc-nitrido complexes as new heart imaging agents. The novel 99mTc radiopharmaceuticals that will be prepared and evaluated in the present project are based upon extremely promising results from our preliminary studies, which clearly demonstrated that we are able to generate and evaluation novel 99mTc radiotracers. These cationic 99mTc-nitrido complexes are designed in such a way that their heart uptake and pharmacokinetics can be optimized by the choice of the bidentate chelator and the bisphosphine coligands. The goal of this project is to obtain sufficient biodistribution data for the successful submission of a future NIH R01 grant application. Accordingly, the SPECIFIC AIMS are: Specific Aim #1. Synthesis and characterization of novel cationic 99mTc-nitrido complexes: impact of the bidentate chelators and bisphosphines on the lipophilicity of their cationic 99mTc-nitrido complexes. Specific Aim #2. Biodistribution studies of cationic 99mTc-nitrido complexes in Sprague-Dawley rats: impact of the bidentate chelators and bisphosphines on their biodistribution properties and excretion patterns. Results from these studies will allow us to select several promising agents for further biological evaluations in the guinea pig model. Specific Aim #3. Biodistribution studies of cationic 99mTc-nitrido complexes in Harley guinea pigs: further demonstration of their utility for myocardial perfusion imaging. If they show high heart uptake and favorable kinetics in the rat and guinea pig models, they would more likely exhibit high heart uptake in humans. Once we are able to achieve the goal of this project, we would conduct more structure-activity relationship studies, evaluate the selected cationic 99mTc-nitrido complexes in diseased animal models, and demonstrate the flow-dependence and linearity of the radiotracer. Diagnostic images showing these regional differences will be extremely useful in identifying areas of poor perfusion. Identification and successful development of better 99mTc perfusion imaging agents will have a profound impact on diagnostic evaluation and therapeutic decision-making in patients with ischemia-related heart diseases, such as coronary artery disease (CAD).