Novel Cationic 99mTc Complexes for Heart Imaging

描述(由申请人提供)： 在目前的临床实践中，放射性核素心肌灌注成像是对已知或可疑冠心病(CAD)患者进行临床评估的重要组成部分。99mTc具有理想的核性质(半衰期和伽马能)和多种配位化学，已成为开发心肌灌注显像剂的首选同位素。99mTc的使用可以在一项研究中同时评估心肌灌注和心功能。自20世纪80年代初以来，人们一直致力于开发亲脂性的TC络合阳离子作为心脏显像剂。作为这些努力的结果，99mTC-Sestamibi和99mTC-Tetrofosmin已被批准为心肌成像的商业产品。尽管它们在临床上得到了广泛的应用，但由于它们的首过萃取率低，肝和肺的本底活度高，至少部分原因是它们没有达到理想的灌注剂的要求。因此，仍然需要更好的99mTc放射性药物来进行心肌灌注成像。 本项目提供了用于心脏成像的新型含冠醚的阳离子99mTc-硝基化合物放射性药物。将在本项目中准备和评估的新放射性药物是基于我们初步研究的非常有希望的结果。这些新的阳离子99mTC-硝基配合物由一个[99TcN]2+核、一个含冠醚的二硫代氨基甲酸酯(冠醚DTC)和一个三膦配体组成。该项目将使用阳离子特性来初始心脏摄取阳离子99mTC-硝基复合体。一旦络合物能够进入细胞，冠醚基团可能会与细胞内的K+相互作用，形成高电荷的99mTc物种，这些物种不能轻易地移出细胞。这种独特的阳离子性质与冠醚基团的存在相结合，可能会产生比99mTC-Sestamibi和99mTC-Tetrofosmin更好的阳离子99mTC-硝基配合物。 本研究的目的是为所提出的阳离子99mTc-硝基配合物提供原理证明。 因此，具体目标是： 1.阳离子99mTc-硝基配合物的合成与表征 2.~(99m)Tc-硝基化合物在SD大鼠体内的生物学评价 3.~(99m)Tc-硝基络合物在雄性哈雷豚鼠体内的生物学评价 4.阳离子Re-硝基配合物的结构表征。 如果它们在大鼠和豚鼠模型中都显示出高的心脏摄取率和有利的动力学，它们在人类的心脏摄取率就更高。一旦基本原则确立，我们将在未来进行更广泛的SAR研究，以探索三膦配体的烷氧基烷基对生物特性(心脏摄取和排泄动力学)的影响。我们的长期目标是开发用于心肌灌注成像的新型Tc络合物放射性药物。新型99mTc灌注显像剂的成功开发将对冠心病患者的诊断评估、风险分层和治疗决策产生深远的影响。

DESCRIPTION (provided by applicant): Myocardial perfusion imaging with radionuclides is an integral component of the clinical evaluation of patients with known or suspected coronary artery disease (CAD) in current clinical practice. 99mTc has been the isotope of choice for the development of myocardial perfusion imaging agents because of its ideal nuclear properties (half-life and gamma-energy) and its diverse coordination chemistry. The use of 99mTc allows simultaneous assessment of myocardial perfusion and cardiac function in a single study. Since early 1980s, extensive research efforts have been directed towards the development of lipophilic Tc complex cations as heart imaging agent. As a result of these efforts, 99mTc-sestamibi and 99mTc-Tetrofosmin have been approved as commercial products for myocardial imaging. Despite their widespread use in clinic, they do not meet the requirements of an ideal perfusion agent at least partially due to their low first-pass extraction and high background activity in liver and lungs. Thus, there is a continuing need for better 99mTc radiopharmaceuticals for myocardial perfusion imaging. This project provides novel crown ether-containing cationic 99mTc-nitrido complex radiopharmaceuticals useful for heart imaging. The new radiopharmaceuticals that will be prepared and evaluated in the present project are based upon very promising results from our preliminary studies. These new cationic 99mTc-nitrido complexes are composed of a [99TcN]2+ core, a crown ether-containing dithiocarbamate (crowned DTC) and a triphosphine coligand. This project will use the cationic character for initial heart uptake of the cationic 99mTc-nitrido complex. Once the complex is able to enter the cell, the crown ether group may interact with intracellular K+ and form highly charged 99mTc species, which are not able to easily move out of the cell. The unique combination of cationic character with the presence of crown ether groups may result in cationic 99mTc-nitrido complexes that are substantially better than 99mTc-Sestamibi and 99mTc-Tetrofosmin. The goal of this research is to provide the proof-of-principle for the proposed cationic 99mTc-nitrido complexes. Accordingly, the SPECIFIC AIMS are: 1. Synthesis and characterization of cationic 99mTc-nitrido complexes. 2. Biological evaluation of cationic 99mTc-nitrido complexes in Sprague-Dawley rats. 3. Biological evaluation of selected cationic 99mTc-nitrido complexes in male Harley guinea pigs. 4. Structural characterization of cationic Re-nitrido complexes. If they show high heart uptake and favorable kinetics in both rat and guinea pig models, they would more likely to have a high heart uptake in humans. Once the basic principle is established, we will conduct more extensive SAR studies to explore the effect of alkoxyalkyl substituents of the triphosphine coliaands on biological properties (heart uptake and excretion kinetics) in the future. Our long-term goal is to develop new Tc complex radiopharmaceuticals for myocardial perfusion imaging. Successful development of new 99mTc perfusion imaging agents will have a profound impact on diagnostic evaluation, risk stratification, and therapeutic decision-making in patients with CAD.