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

描述(由申请人提供)：与缺血相关的疾病占全球死亡人数的大部分。心肌缺血是一种严重的情况，缺血组织再灌注的延迟可能危及生命。这在老年人口中尤其如此。因此，快速、准确地早期检测心肌缺血是非常必要的，以便在不可逆转的心肌损伤发生之前给予各种治疗方案。本项目是关于新型阳离子99mTc-硝基配合物作为新的心脏显像剂的应用。本项目将制备和评估的新型99mTc放射性药物是基于我们的初步研究中非常有希望的结果，这些结果清楚地表明我们能够产生和评估新型99mTc放射性示踪剂。这些阳离子99mTC-硝基配合物的设计方式是，通过选择双齿螯合剂和双膦配体，可以优化它们的心脏摄取和药物动力学。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 R01拨款申请。因此，具体目标是：特定目标#1.新型阳离子99mTC-硝基配合物的合成与表征：双齿螯合剂和双膦试剂对其阳离子99mTC-硝基配合物亲油性的影响。特定目标#2.阳离子99mTC-硝基配合物在SD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希望的药物来进一步在豚鼠模型中进行生物学评估。具体目标#3.阳离子99mTC-硝基复合体在哈雷豚鼠体内的生物分布研究：进一步证明其在心肌灌注成像中的作用。如果它们在大鼠和豚鼠模型中表现出高心脏摄取率和有利的动力学，它们更有可能在人类身上表现出高心脏摄取率。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，在疾病动物模型中评估选定的阳离子99mTc-硝基配合物，并展示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将对识别血流灌注不良的区域非常有用。更好的99mTc灌注显像剂的发现和成功开发将对冠心病(CAD)等缺血性心脏病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).