Novel Cationic 99mTc Complexes for Heart Imaging

描述（由申请人提供）： 放射性核素心肌灌注成像是目前临床实践中已知或疑似冠状动脉疾病（CAD）患者临床评价的一个组成部分。99 mTc由于其理想的核性质（半衰期和γ能量）及其多样的配位化学，一直是开发心肌灌注显像剂的首选同位素。使用99 mTc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，广泛的研究努力已经指向开发亲脂性Tc络合物阳离子作为心脏显像剂。作为这些努力的结果，99 mTc-司他米比和99 mTc-替曲膦已被批准作为心肌成像的商业产品。尽管它们在临床上广泛使用，但它们不满足理想灌注剂的要求，至少部分是由于它们的低首过提取和在肝和肺中的高背景活性。因此，持续需要更好的99 mTc放射性药物用于心肌灌注成像。 本项目提供了用于心脏成像的新型含冠醚的阳离子99 mTc-腈基复合物放射性药物。在本项目中将制备和评价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~（99）mTc-氮配合物由~（99）TcN ~（2+）核、含冠醚的二硫代氨基甲酸酯（冠醚DTC）和三膦配体组成。本项目将使用阳离子99 mTc-硝基络合物的初始心脏摄取的阳离子特性。一旦络合物能够进入细胞，冠醚基团可以与细胞内K+相互作用并形成高电荷的99 mTc物质，其不能容易地移出细胞。阳离子特性与冠醚基团的存在的独特组合可导致阳离子99 mTc-次氮基络合物，其显著优于99 mTc-塞他米比和99 mTc-替曲膦。 本研究的目的是为所提出的阳离子99 mTc-氮化物配合物提供原理验证。 因此，具体目标是： 1.阳离子~（99）mTc-硝基配合物的合成与表征 2.阳离子99 mTc-亚硝基配合物在Sprague-Dawley大鼠中的生物学评价。 3.在雄性哈雷豚鼠中选择的阳离子99 mTc-硝基络合物的生物学评价。 4.阳离子Re-氮化物配合物的结构表征。 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具有高心脏摄取。一旦基本原理建立，我们将进行更广泛的SAR研究，以探索三膦coliaands的烷氧基烷基取代基对生物学特性（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显像的新的Tc络合物放射性药物。新的99 mTc灌注显像剂的成功开发将对CAD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.