Monosubstituted [M(N)Cl(2)(POP)] [M = Tc, 1; Re, 2] and [M(N)Cl(2)(PNP)] [M = Tc, 3; Re, 4] complexes were prepared by reaction of the precursors [M(N)Cl(4)](-) and [M(N)Cl(2)(PPh(3))(2)] (M = Tc, Re) with the diphosphine ligands bis(2-diphenylphosphinoethyl)ether (POP) and bis(2-diphenylphosphinoethyl)methoxyethylamine (PNP) in refluxing dichloromethane/methanol solutions. In these compounds, the diphosphine acted as a chelating ligand bound to the metal center through the two phosphorus atoms. Considering also the weak interaction of the heteroatom (N or O) located in the middle of the carbon backbone connecting the two P atoms, we found that the coordination arrangement of the diphosphine ligand could be viewed as either meridional (m) or facial (f), and the resulting geometry as pseudooctahedral. The heteroatom of the diphosphine ligand was invariably located trans to the nitrido linkage, as established by X-ray diffraction analysis of the representative compounds 2m and 4f. Density functional theoretical calculations showed that in POP-type complexes the mer form is favored by approximately 6 kcal mol(-1), whereas mer and fac isomers are almost isoenergetic in PNP-type complexes. A possible role of noncovalent interactions between the phosphinic phenyl substituents in stabilizing the fac-isomer was also highlighted. The existence of fac-mer isomerism in this class of complexes was attributed to the strong tendency of the two phosphorus atoms to occupy a reciprocal trans-position within the pseudooctahedral geometry. The switching of P atoms between cis- and trans-configurations was confirmed by the observation that the fac isomers, 1f and 2f, were irreversibly transformed, in solution, into the corresponding mer isomers, 1m and 2m, thus suggesting that fac complexes are more reactive species. Theoretical calculations supported this view by showing that the lowest unoccupied orbitals of the fac isomers are more accessible to a nucleophilic attack with respect to those of the mer ones. Furthermore, the large participation of the Cl orbitals to the HOMO, which is a metal-ligand pi* antibonding in the complex basal plane, shows that the Tc-Cl bonds are labile. As a consequence, facial isomers could be considered as highly electrophilic intermediates that were selectively reactive toward substitution by electron-rich donor ligands. Experimental evidence was in close agreement with this description. It was found that fac-[M(N)Cl(2)(PXP)] complexes easily underwent ligand-exchange reactions with bidentate donor ligands such as mercaptoacetic acid (NaHL(1)), S-methyl 2-methyldithiocarbazate (H(2)L(2)), diethyldithiocarbamate sodium salt (NaL(3)), and N-acetyl-L-cysteine (H(2)L(4)) to afford stable asymmetrical heterocomplexes of the type fac-[M(N)(L(n))(POP)](+/0) (5-8) and fac-[M(N)(L(n))(PNP)](+/0) (9-14) comprising two different polydentate chelating ligands bound to the same metal center. In these reactions, the bidentate ligand replaced the two chloride atoms on the equatorial plane of the distorted octahedron,...
Copper radionuclides are rapidly emerging as potential diagnostic and therapeutic tools in oncology, particularly Cu-radiopharmaceuticals for targeting neuroendocrine, prostate, and hypoxic tumors. Unexpectedly, experimental results are also revealing the impressive biological behavior of simple [Cu] ions. For example, it has been demonstrated that administration of ionic [Cu] in physiological solution allows the selective targeting of a variety of malignancies. These remarkable biological properties appear to be crucially linked to the natural role of copper ions in cell proliferation. Here, we review the current status of Cu-radiopharmaceuticals in molecular imaging and cancer therapy.
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.
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