A class of asymmetrical nitrido 99mTc heterocomplexes as heart imaging agents with improved biological properties

Abstract

Asymmetrical heterocomplexes containing a terminal technetium-nitrogen multiple bond coordinated to one diphosphine ligand (PNP) and one dithiocarbamate ligand (DBODC), were obtained through a simple two-step procedure under controlled conditions. The resulting complexes [99mTc(N)(PNP)(DBODC)]+ are monocationic, and possess a distorted square-pyramidal geometry where the Tc triple bond N multiple bond occupies an apical position and the diphosphine and dithiocarbamate ligands span the residual four coordination positions on the basal plane through the two phosphorus atoms and the two sulfur atoms, respectively. Biodistribution data in rats demonstrated that these complexes were rapidly extracted by the myocardium, and retained in this region for a prolonged time. After a few minutes post-injection, lung uptake became negligible, and liver washout was extremely rapid and quantitative. Analysis of heart/liver uptake ratios for these complexes revealed that their values increased exponentially in time, and after 60 min post-injection liver activity was almost completely eliminated into the intestine. Comparison with heart/liver ratios determined for 99mTc sestamibi and 99mTc tetrfosmin showed that values for these latter compounds were approximately 10 times lower than those measured for [99mTc(N)(PNP)(DBODC)]+ complexes at 60 min post-injection. In conclusion, the monocationic tracers [99mTc(N)(PNP)(DBODC)]+ exhibit high myocardial uptake in rats and dramatically high heart/lung and heart/liver ratios, suggesting that this novel class of perfusion agents could be conveniently employed to obtain heart images with superior imaging quality.

Subcellular Distribution and Metabolism Studies of the Potential Myocardial Imaging Agent [99mTc(N)(DBODC)(PNP5)]+

“…Differences between the observed values of heart uptake reported here in female rats and previous data in the literature (2,3,18) could be attributed to differences in the composition of the injected solution. In particular, in our work we used a saline solution containing less than 5% (v/v) ethanol whereas other groups used a phosphate buffer solution (0.1 mol dm 21 ; pH 7.4) containing 10% (v/v) ethanol (2,3) or a saline solution containing 15% (w/w) propylene glycol (18).…”

“…Previ ously, we reported a new class of nitrido 99m Tc agents of the type [ 99m Tc(N)(DTC)(PNP)] 1 , where DTC is a dithiocarbamate ligand and PNP an aminodiphosphine ligand, as potential myocardial imaging agents (1)(2)(3). Among the tested compounds, [ 99m Tc(N)(DBODC)(PNP5)] 1 and [ 99m Tc(N)(DBODC)(PNP3)] 1 ( Fig.…”

Impact of Bidentate Chelators on Lipophilicity, Stability, and Biodistribution Characteristics of Cationic 99mTc-Nitrido Complexes

“…The difference in the heart uptake of cationic 99m Tc radiotracers is most likely caused by their lipophilicity and capability to across the plasma and mitochondrial membranes. Cationic 99m Tc radiotracers with the log P>1.5 often have a low heart uptake and a slow liver clearance while more hydrophilic cationic radiotracers with log P<0 tend to show fast washout from the myocardium (1)(2)(3)(22)(23)(24)(25). In both cases, the heart/liver ratio is low because of either high liver uptake or fast myocardial washout.…”

Whole-Body Biodistribution and Radiation Dosimetry of the New Cardiac Tracer 99mTc-N-DBODC

“…However, a dramatic difference was observed in liver washout, which was remarkably rapid and quantitative. In particular, at 60 min after injection in rats, the heart-to-liver ratio of 99m Tc-N-DBODC was approximately 10 times higher than that of 99m Tcsestamibi and 99m Tc-tetrofosmin (2)(3)(4). On the basis of these promising results, this study was designed to evaluate the safety profile and the biodistribution of 99m Tc-N-DBODC in healthy human volunteers under both stress and rest conditions.…”

“…1) was studied extensively in rats (3,4) and dogs (5) and compared with that of the commercial radiopharmaceuticals 99m Tc-sestamibi (Cardiolite; Bristol-Myers Squibb Medical Imaging, Inc.) and 99m Tctetrofosmin (Myoview; GE Healthcare). These results in animals showed that heart uptake of 99m Tc-N-DBODC and washout from blood and lungs, as well as kinetic behavior as determined in dogs, are similar to those of the other 2 cardiac agents (5).…”