64^Cu-bis(thiosemicarbazone) Complexes for Delineating Myocardial Hypoxia
Coronary artery disease and coronary microvascular disease, as well as acute myocardial infarction and adverse remodelling are often characterised by tissue hypoxia. They benefit from the earliest possible diagnosis and treatment. Positron Emission Tomography (PET) is a highly sensitive technique capable of non-invasively imaging the biochemistry of the body, with the capacity to track biochemical changes over time. In this project, we aim to characterise a series of novel PET imaging agents able to identify and characterise hypoxic myocardium with a view to optimising the treatment of a range of cardiovascular diseases. Bisthiosemicarbazone (BTSC) ligands readily chelate positron emitting copper isotopes, and have been demonstrated to selectively accumulate in hypoxic tissue in vitro, in vivo, and in isolated perfused hearts. While the lead compound Cu-ATSM has been widely investigated, a library of related Cu-BTSC complexes exist which may have better pharmacokinetics and selectivity for application in cardiology. We employed isolated ventricular myocytes and isolated perfused hearts to screen a number of 64Cu-labelled BTSC complexes, to assess their hypoxia selectivity and accumulation in cardiac tissue. For this purpose we developed a novel incubation chamber for maintaining isolated cardiomyocytes under hypoxic conditions. We also developed a novel gamma radiation detector array comprising three Na/1 y-detectors, for monitoring the flow of radioactivity through isolated perfused hearts in real-time. We have demonstrated the hypoxia selective accumulation of 6 Cu-ATSM in adult rat ventricular myocytes (ARVM) incubated under hypoxic conditions. Using isolated perfused hearts we demonstrated that all 64Cu-BTSC readily accumulate within cardiac tissue in an oxygen-dependent manner. We have demonstrated the hypoxia selective accumulation of 64Cu-ATSM in adult rat ventricular myocytes (ARVM) incubated under hypoxic conditions. Using isolated perfused hearts we demonstrated that all 64Cu-BTSC readily accumulate within cardiac tissue in an oxygen-dependent manner. We also identified a relationship between the structure of Cu-BTSCs and their tissue retention, with lower molecular weight complexes providing the greatest hypoxic to oxygenated tissue contrast. In doing this we have identified two complexes, Cu-ATS and Cu-CTS, which could potentially supersede Cu-ATSM as the agent of choice for imaging the hypoxic myocardium.
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