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

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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).