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

The preparation, characterization and first biological evaluation in rats of a novel class of monocationic Tc-99m heart imaging agents are reported. The complexes are represented by the general formula [99mTc(N)(PNP)(L)]+, where L is the monoan-ionic form of a dithiocarbamate ligand of the type [R1(R2)-N-C(=S)S]-, and PNP is a diphosphine ligand of the type [(R3)2P-(CH2)2]2-N(R4) (R1-4 = organic functional groups). Methods: The new complexes were prepared using both liquid and freeze-dried formulations through a 2-step procedure. The first step involved the formation of the [TcßN]2+ group through the reaction of [99mTcO4]- with succinic dihydrazide (SDH) as a donor of nitride nitrogen atoms (N3-) in the presence of Sn2+ ions. This 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 prod-ucts [99mTc(N)(PNP)(L)]+. The chemical identity of the resulting Tc-99m complexes was determined by comparing their chromatographic properties with those of the cor-responding 99gTc analogs prepared using the long-lived isotope Tc-99g and charac-terized by spectroscopic and crystallographic techniques. Ex-vivo biodistribution studies were conducted in rats. In-vivo tomographic images of rat.s heart were ob-tained using a small-animal SPET scanner Results: The complexes [99mTc(N)(PNP)(L)]+ are monocationic and possess a distorted square-pyramidal ge- ometry where the TcßN multiple bound occupies an apical position and the di-phosphine and dithiocarbamate ligands span the residual four coordination positions on the basal plane through the two phosphorus atoms and the two sulfur atoms, re-spectively. Imaging and biodistribution studies demonstrated that these radiopharma- ceuticals localize selectively into the myocardium of rats, and are retained in this re-gion for a prolonged time. Kinetics of heart uptake and clearance were found to be influenced by the variation of the lateral R1-4 groups. Blood and lung washouts were extremely fast. Elimination occurred mostly through the kidneys and the liver. Sur-prisingly, after one hour from injection, liver activity was almost negligible. Analysis of heart/liver and heart/lung uptake ratios showed that these values increase exponen-tially in time, and become much higher than those determined for 99mTc-Sestamibi and 99mTc-Tetrofosmin. These findings were confirmed by analysis of high-quality SPET images collected in rats for the new complexes and compared with images ob-tained with 99mTc-Sestamibi and 99mTc-Tetrofosmin. Conclusion: The high myocar-dial uptake combined with the very high value of heart/lung and heart/liver ratios indicate that the complexes [99mTc(N)(PNP)(L)]+ exhibit very favorable distribution properties and could be potentially used to obtain SPET cardiac images with improved quality.