Development of technetium-99m-complexes of hydroxy-4-pyrones as potential myocardial imaging agents

(Tl-201) -Thallous chloride, the most widely used myocardial imaging agent is far from being ideal because of the inferior physical characteristics of Thallium-201. Technetium-99m is an isotope with superior characteristics, and recently has been the focus of development of cationic myocardial agents. The quest for a cationic Tc-99m-complex for imaging the heart continues even after the introduction of Tc-99-Sestamibi (Cardiolite, DuPont) and Tc-99m-Teboroxime (Cardiotec, Squibb), because all the needs of diagnostic cardiology have not been satisfied. A new class of Technetium-99m-complexes was developed, using hydroxy-4-pyrone derivatives as parent ligands. The potential of these compounds as myocardial imaging agents was evaluated. The charge on these complexes was studied using cellulose polyacetate electrophoresis. The lipophilicity of the labeled compounds was studied as a measure of myocardial and hepatic uptake, using the octanol-water partition coefficient method. To understand the extent of blood retention of these complexes, their protein-binding was studied in vitro using rabbit blood. Whole body scintigraphy was performed in the rabbit to explore the biodistribution patterns of the Tc-99m-hydroxy-4-pyrones, as well as their structure-biodistribution relationship. Fifteen compounds were evaluated, divided into three subclasses of hydroxy-4-pyrone derivatives, namely, the 2-substituted, the 6-substituted, and the fused-ring derivatives. Seven compounds were shown to form cationic complexes with Tc-99m. Generally, compounds with a nitrogen-containing heterocyclic 6-substituent in the parent ligand showed promising biodistribution patterns. Labeled compounds containing a 2-substituent did not offer a good separation of the myocardial and hepatic radioactivity. Compounds containing aromatic substituents were found to be more lipohilic. This led to their predominantly hepatobiliary disposition. The hydrophilic compounds were mainly excreted by the kidneys. Among the 6-substituted compounds, Tc-99m-2-hydroxymethyl-6(4-methylpiperazinomethyl)-5-hydroxy-4-pyrone (compound IX), and Tc-99m-2-hydroxymethyl-6-piperidinomethyl-5-hydroxy-4-pyrone (compound X) appear to be the best candidates from this class of cationic Tc-99m-complexes for imaging the myocardium. Compound IX showed the best separation between the myocardial and liver radioactivity among all the fifteen compounds. The elimination of both these compounds from the myocardial area was estimated to occur with a half-life ranging between that of Cardiolite (which is virtually uncleared) and Cardiotec (which is eliminated rapidly). With an acceptable heart-to-liver ratio of radioactivity, and an intermediate elimination half-life compared to what is presently available, these two compounds hold promise to offer an alternative in diagnostic cardiological procedures.