Technetium and Rhenium in Five-Coordinate Symmetrical and Dissymmetrical Nitrido Complexes with Alkyl Phosphino-thiol Ligands. Synthesis and Structural Characterization

The reactivity of bulky alkylphosphino-thiol ligands (PSH) toward nitride-M(V, VI) (M = Tc/Re) precursors was investigated. Neutral five-coordinate monosubstituted complexes of the type [M(N)(PS)Cl(PPh3)] (Tc1−4, Re1−2) were prepared in moderate to high yields. It was found that these [M(N)(PS)Cl(PPh3)] species underwent ligand-exchange reactions under mild conditions when reacted with bidentate mononegative ligands having soft donor atoms such as dithiocarbamates (NaLn) to afford stable dissymmetrical mixed-substituted complexes of the type [M(N)(PS)(Ln)] (Tc5,8−10, Re5−9) containing two different bidentate chelating ligands bound to the [MN]2+ moiety. In these reactions, the dithiocarbamate replaced the two labile monodentate ligands (Cl and PPh3) leaving the [M(N)(PS)]+ building block intact. In the above reactions, technetium and rhenium were found to behave in a similar way. Instead, under more drastic conditions, reactions of PSH with [M(N)Cl2(PPh3)2] gave a mixture of monosubstituted [M(N)(PS)Cl(PPh3)] and bis-substituted species [M(N)(PS)2] (Tc11−14) in the case of technetium, whereas only monosubstituted [M(N)(PS)Cl(PPh3)] complexes were recovered for rhenium. All isolated products were characterized by elemental analysis, IR and multinuclear (1H, 13C, and 31P) NMR spectroscopies, ESI MS spectrometry, and X-ray crystal structure determination of the representative monosubstituted [Tc(N)(PStbu)Cl(PPh3)] (Tc4) and mixed-substituted [Re(N)(PScy)(L3)] (Re7) and [Re(N)(PSiso)(L4)] (Re9) complexes. The latter rhenium complexes represent the first example of a square-pyramidal nitrido Re species with the basal plane defined by a PS3 donor set. Monosubstituted [M(N)(PS)Cl(PPh3)] species bearing the substitution-inert [M(N)(PS)]+ moieties act as suitable building blocks proposed for the construction of new classes of dissymmetrical nitrido compounds with potential application in the development of essential and target specific 99mTc and 188Re radiopharmaceuticals for imaging and therapy, respectively

Biological <i>in Vitro</i> and <i>in Vivo</i> Studies of a Series of New Asymmetrical Cationic [^99mTc(N)(DTC-Ln)(PNP)]⁺ Complex (DTC-Ln = Alicyclic Dithiocarbamate and PNP = Diphosphinoamine)

99mTc(N)-DBODC5 is a cationic mixed compound under clinical investigation as potential myocardial imaging agent. In spite of this, analogously to the other cationic 99mTc-agents, presents a relatively low first-pass extraction. Thus, modification of 99mTc(N)-DBODC(5) direct to increase its first-pass extraction keeping unaltered the favorable imaging properties would be desirable. This work describes the synthesis and biological evaluation of a series of novel cationic 99mTc-nitrido complexes, of general formula [99mTcN(DTC-Ln)(PNP)]+ (DTC-Ln= alicyclic dithiocarbamates; PNP = diphosphinoamine), as potential radiotracers for myocardial perfusion imaging. The synthesis of cationic 99mTc-(N)-complexes were accomplished in two steps. Biodistribution studies were performed in rats and compared with the distribution profiles of 99mTc(N)-DBODC5 and 99mTc-Sestamibi. The metabolisms of the most promising compounds were evaluated by HPLC methods. Biological studies revealed that most of the complexes have a high initial and persistent heart uptake with rapid clearance from nontarget tissues. Among tested compounds, 2 and 12 showed improved heart uptake with respect to the gold standard 99mTc-complexes with favorable heart-to-liver and slightly lower heart-to-lung ratios. Chromatographic profiles of 99mTc(N)-radioactivity extracted from tissues and fluids were coincident with the native compound evidencing remarkable in vivo stability of these agents. This study shows that the incorporation of alicyclic dithiocarbamate in the [99mTc(N)(PNP)]+ building block yields to a significant increase of the heart uptake at early injection point suggesting that the first-pass extraction fraction of these novel complexes may be increased with respect to the other cationic 99mTc-agents keeping almost unaltered the favorable target/nontarget ratios