The primary objective of this research is the development of new, efficacious, myocardial perfusion imaging agents based on the chemistry and nuclear properties of 99m-Tc. This will be accomplished by merging the techniques, equipment and expertise of inorganic chemistry with those of nuclear medicine. Emphasis will be on (1) elucidation of the inorganic chemistry of technetium, utilizing the relatively stable isotope 99-Tc and physical techniques such as single crystal x-ray diffraction and thin-layer spectroelectrochemistry which require only very small quantities of sample, (2) development of synthetic routes to 99m-Tc radiopharmaceuticals that do not involve Sn(II) reduction, (3) development of 99m-Tc myocardial perfusion imaging agents based on well defined, monocationic technetium complexes, (4) elucidation of the chemistry and mechanism of action of those monocationic 99m-Tc myocardial perfusion imaging agents recently developed within this project, e.g. (99m-Tc(dmpe)2Cl2)+ and (99m-Tc(dmpe)3)+ where dmpe = 1,2-bis(dimethylphosphine)ethane, (5) development of in vitro screening procedures to aid in selecting which monocationic 99m-Tc complexes warrant extensive in vivo evaluation, and (6) design and synthesis of new classes of technetium radiopharmaceuticals, the molecular and chemical properties of which can be subtly and systematically modified in order to increase specificity for the myocardium. Animal testing, including the imaging of dogs with induced acute myocardial infarction, will be used to evaluate the efficacy of new radiopharmaceuticals and thereby delineate those molecular and chemical properties than enhance myocardial uptake. The most promising myocardial perfusion imaging agents will be evaluated in human subjects.
