Synthesis and biologic evaluation of monocationic asymmetric Tc-99-Nitride heterocomplexes showing high heart uptake and improved imaging properties

The preparation, characterization, and first biologic evaluation in rats of a novel class of monocationic 99mTc heart imaging agents are reported. The complexes are represented by the general formula [99mTc(N)(PNP)(L)], where L is the monoanionic form of a dithiocarbamate ligand of the type [R1(R2)-N-C(S)S], PNP is a diphosphine ligand of the type [(R3)2P-(CH2)2]2-N(R4), and R1–R4 are organic functional groups. Methods: The new complexes were prepared by use of both liquid and freeze-dried formulations through a 2-step procedure. The first step involved the formation of the [Tc'N]2 group through the reaction of 99mTcO4 with succinic dihydrazide as a donor of nitride nitrogen atoms (N3) in the presence of Sn2 ions. This step was followed by the simultaneous addition to the reaction solution of the ligand PNP and of the sodium salt of the dithiocarbamate ligand (NaL) to afford the final products, [99mTc(N)(PNP)(L)]. The chemical identities of the resulting 99mTc complexes were determined by comparing their chromatographic properties with those of the corresponding 99gTc analogs prepared by use of the longlived isotope 99gTc and characterized by spectroscopic and crystallographic techniques. Ex vivo biodistribution studies were conducted in rats. In vivo tomographic images of the rat heart were obtained by use of a small-animal SPECT scanner. Results: The [99mTc(N)(PNP)(L)] complexes are monocationic and possess a distorted square–pyramidal geometry in which the Tc'N multiple bond occupies an apical position and the diphosphine and dithiocarbamate ligands span the residual 4 coordination positions on the basal plane through the 2 phosphorus atoms and the 2 sulfur atoms, respectively. Imaging and biodistribution studies demonstrated that these radiopharmaceuticals localize selectively in the myocardium of rats and are retained in this region for a prolonged time. The kinetics of heart uptake and clearance were found to be influenced by variations in the lateral R1–R4 groups. Blood and lung washouts were extremely fast. Elimination occurred mostly through the kidneysand the liver. Surprisingly, at 1 h after injection, liver activity was almost negligible. Analysis of heart-to-liver and heart-to-lung uptake ratios showed that these values increased exponentially over time and became much higher than those determined for 99mTc-sestamibi and 99mTc-tetrofosmin. These findings were confirmed by analysis of high-quality SPECT images collected in rats for the new complexes and compared with images obtained with 99mTc-sestamibi and 99mTc-tetrofosmin. Conclusion: The high myocardial uptake and the very high heart-to-lung and heart-to-liver uptake ratios indicate that the [99mTc(N)(PNP)(L)] complexes exhibit very favorable distribution properties and could be used to obtain SPECT cardiac images with improved quality