Oxorhenium(V) and Oxotechnetium(V) [NN][S]₃ Complexes of 2-Phenylbenzothiazole Derivatives

The reaction of 2-(2‘-pyridyl)benzothiazole, [NN], with the ReO(V)3+ and TcO(V)3+ cores in the presence of thiophenols, [S] (RC6H4SH, R = H, 4-CH3, 4-OCH3), as coligands led to the isolation of hexacoordinated complexes of the MO[NN][S]3 type (M = Re, Tc). In all cases, two geometric mer isomers were formed, as evidenced by NMR spectroscopy and confirmed by X-ray crystallography. In both isomers, the coordination geometry about the metal ion is a distorted octahedral defined by the two nitrogen atoms of the bidentate ligand, the three sulfur atoms of the monodentate thiols, and the oxygen atom of the oxo group. The apical positions of the octahedron are occupied by the oxygen of the oxo group and, in one of the isomers, the nitrogen of the pyridyl moiety of 2-(2‘-pyridyl)benzothiazole, while, in the second isomer, the imine nitrogen of 2-(2‘-pyridyl)benzothiazole. The complexes are stable, neutral, and lipophilic. Complete 1H and 13C NMR assignments are reported for all complexes. The synthetic reaction was also successfully transferred at the technetium-99m tracer level by ligand exchange reaction using 99mTc−glucoheptonate as precursor in the presence of 2-(2‘-pyridyl)benzothiazole and 4-CH3C6H4SH. The structure of the technetium-99m complex was established by high-performance liquid chromatographic comparison with the analogous oxotechnetium and oxorhenium complexes. The 2-(2‘-pyridyl)benzothiazole ligand serves as a preliminary model for 2-(4-aminophenyl)benzothiazole, which possesses interesting properties for the development of technetium and rhenium radiopharmaceuticals for tumor imaging and/or radiotherapy as well as in vivo diagnosis of Alzheimer's disease

Oxorhenium(V) and Oxotechnetium(V) [NN][S]₃ Complexes of 2-Phenylbenzothiazole Derivatives

The reaction of 2-(2‘-pyridyl)benzothiazole, [NN], with the ReO(V)3+ and TcO(V)3+ cores in the presence of thiophenols, [S] (RC6H4SH, R = H, 4-CH3, 4-OCH3), as coligands led to the isolation of hexacoordinated complexes of the MO[NN][S]3 type (M = Re, Tc). In all cases, two geometric mer isomers were formed, as evidenced by NMR spectroscopy and confirmed by X-ray crystallography. In both isomers, the coordination geometry about the metal ion is a distorted octahedral defined by the two nitrogen atoms of the bidentate ligand, the three sulfur atoms of the monodentate thiols, and the oxygen atom of the oxo group. The apical positions of the octahedron are occupied by the oxygen of the oxo group and, in one of the isomers, the nitrogen of the pyridyl moiety of 2-(2‘-pyridyl)benzothiazole, while, in the second isomer, the imine nitrogen of 2-(2‘-pyridyl)benzothiazole. The complexes are stable, neutral, and lipophilic. Complete 1H and 13C NMR assignments are reported for all complexes. The synthetic reaction was also successfully transferred at the technetium-99m tracer level by ligand exchange reaction using 99mTc−glucoheptonate as precursor in the presence of 2-(2‘-pyridyl)benzothiazole and 4-CH3C6H4SH. The structure of the technetium-99m complex was established by high-performance liquid chromatographic comparison with the analogous oxotechnetium and oxorhenium complexes. The 2-(2‘-pyridyl)benzothiazole ligand serves as a preliminary model for 2-(4-aminophenyl)benzothiazole, which possesses interesting properties for the development of technetium and rhenium radiopharmaceuticals for tumor imaging and/or radiotherapy as well as in vivo diagnosis of Alzheimer's disease

Glutathione-Mediated Metabolism of Technetium-99m SNS/S Mixed Ligand Complexes: A Proposed Mechanism of Brain Retention

Two series of [99mTc](SNS/S) mixed ligand complexes each carrying the N-diethylaminoethyl or the N-ethyl-substituted bis(2-mercaptoethyl)amine ligand (SNS) are produced at tracer level using tin chloride as reductant and glucoheptonate as transfer ligand. The identity of [99mTc](SNS/S) complexes is established by high-performance liquid chromatographic (HPLC) comparison with authentic rhenium samples. The para substituent R on the phenylthiolate coligand (S) ranges from electron-donating (−NH2) to electron-withdrawing (−NO2) groups, to study complex stability against nucleophiles as a result of N- and R-substitution. The relative resistance of [99mTc](SNS/S) complexes against nucleophilic attack of glutathione (GSH), a native nucleophilic thiol of 2 mM intracerebral concentration, is investigated in vitro by HPLC. The reaction of [99mTc](SNS/S) complexes with GSH is reversible and advances via substitution of the monothiolate ligand by GS- and concomitant formation of the hydrophilic [99mTc](SNS/GS) daughter compound. The N-diethylaminoethyl complexes are found to be more reactive against GSH as compared to the N-ethyl ones. Complex reactivity as a result of R-substitution follows the sequence −NO2 ≫ −H > −NH2. These in vitro findings correlate well with in vivo distribution data in mice. Thus, brain retention parallels complex susceptibility to GSH attack. Furthermore, isolation of the hydrophilic [99mTc](SNS/GS) metabolite from biological fluids and brain homogenates provides additional evidence that the brain retention mechanism of [99mTc](SNS/S) complexes is GSH-mediated

Synthesis, Characterization, and Biological Evaluation of M(I)(CO)₃(NNO) Complexes (M = Re, ^99mTc) Conjugated to 2-(4-Aminophenyl)benzothiazole as Potential Breast Cancer Radiopharmaceuticals

The synthesis and biological evaluation of new M(I)(CO)3(NNO) (M = Re, 99mTc) complexes attached to the antitumor agent 2-(4-aminophenyl)benzothiazole are reported. The fluorescent rhenium complex enters MCF-7 breast cancer cells but does not enter normal HFFF-2 and MRC-5 cells. The analogous radioactive 99mTc complex produces fast blood and soft tissue clearance when administered to healthy mice. These complexes are promising candidates for developing radiopharmaceuticals for imaging (99mTc) and targeted radiotherapy (186Re, 188Re) of breast cancer

New Oxorhenium(V) Complexes from the Widely Used Diaminedithiol (DADT) Ligand System

Synthesis of the 2,9-dimethyl-4,7-diaza-4-alkyl-2,9-decanedithiol (1, alkyl = morpholinylethyl in a, and alkyl = pyrrolidinylethyl in b), following a widely used synthetic scheme for diaminedithiol (DADT) ligands, led to the isolation of 1-alkyl-2-(1‘-methyl-1‘-sulfanylethyl)-3-(2‘ ‘-methyl-2‘ ‘-sulfanylpropyl)diazolidine (3) as the major product. Both ligands 1 and 2 gave complexes with the oxorhenium ReO(V) core. Ligand 1 gave the expected ReO[SNNS] complex (2) with the side chain on nitrogen in the syn configuration. Ligand 3 gave, in the presence of a monodentate aromatic thiol, complexes of the ReO[SNN][S][S] (4) and ReO[SNN][S] type (5), respectively, in which the diazolidine ring has rearranged to a thiazolidine ring. Crystallographic analysis showed that in 4 the coordination geometry about the metal is distorted octahedral where the equatorial plane is defined by the sulfur and one of the nitrogen atoms of the ligand and the two sulfurs of the aromatic thiols, while the axial positions are occupied by the oxygen of the ReO core and the second nitrogen of the ligand. Specifically, complex 4a crystallizes in space group P21/c, a = 15.63(1) Å, b = 15.28(2) Å, c = 16.07(1) Å, β = 113.78(2)°, V = 3512(5) Å3, Z = 4. Complex 4b crystallizes in space group P21/n, a = 14.560(9) Å, b = 14.804(9) Å, c = 19.85(1) Å, β = 90.94(2)°, V = 4278(1) Å3, Z = 4. In 5b, the coordination geometry is distorted square pyramidal with the SNN donor atom of the ligand and the aromatic thiol defining the equatorial plane and the doubly bonded oxygen occupying the apex of the pyramid. Complex 5b crystallizes in space group P1̄, a = 9.387(5) Å, b = 11.306(5) Å, c = 14.040(6) Å, α = 84.51(1)°, β = 84.45(2)°, γ = 87.17(1)°, V = 1475(1) Å3, Z = 2. All isolated complexes are neutral and lipophilic. Complete assignments of 1H and 13C NMR resonances are reported

Synthesis and Characterization of Novel Oxotechnetium (⁹⁹Tc and ^99mTc) and Oxorhenium Complexes from the 2,2‘-Bipyridine (NN)/Thiol (S) Mixed-Ligand System

The synthesis and characterization of oxotechnetium and oxorhenium mixed-ligand complexes of the general formula MO[NN][S]3 (M = 99Tc and Re), where NN represents the bidentate ligand 2,2‘-bipyridine and S represents a monodentate thiophenol, is reported. The complexes were prepared by ligand exchange reactions using 99Tc-gluconate and ReOCl3(PPh3)2 as precursors for the oxotechnetium and oxorhenium complexes, respectively. Compound 1 (M = 99Tc, S = 4-methylthiophenol) crystallizes in the monoclinic space group P21/a, a = 23.12(1) Å, b = 14.349(6) Å, c = 8.801(4) Å, β = 94.81(2)°, V = 2918(2) Å3, Z = 4. Compound 3 (M = Re, S = 4-methylthiophenol) crystallizes in the monoclinic space group P21/a, a = 23.018(9) Å, b = 14.421(5) Å, c = 8.775(3) Å, β = 94.78(1)°, V = 2903(2) Å3, Z = 4. Compound 4 (M = Re, S = 4-methoxythiophenol) crystallizes in the orthorhombic space group Pbca, a = 16.32(1) Å, b = 24.55(2) Å, c = 16.94(1) Å, V = 6788(9) Å3, Z = 8. In all cases, the coordination geometry around the metal is distorted octahedral with the equatorial plane being defined by the three sulfur atoms of the thiophenols and one nitrogen atom of 2,2‘-bipyridine, while the apical positions are occupied by the second nitrogen atom of 2,2‘-bipyridine and the oxygen of the MO core. The complexes are stable, neutral, and lipophilic. Complete 1H and 13C NMR assignments are reported for all complexes. The analogous oxotechnetium complexes have been also synthesized at tracer level (99mTc) by mixing the 2,2‘-bipyridine and the corresponding thiol with Na99mTcO4 generator eluate using NaBH4 as reducing agent. Their structure was established by chromatographic comparison with authentic oxotechnetium and oxorhenium complexes using high performance liquid chromatography techniques

Evaluation of Re and ^99mTc Complexes of 2-(4′-Aminophenyl)benzothiazole as Potential Breast Cancer Radiopharmaceuticals

The synthesis of M(I)(CO)3(NNO) (M = Re, 99mTc) complexes conjugated to the antitumor agent 2-(4′-aminophenyl)benzothiazole and to its 6-methyl derivative, as well as their in vitro and in vivo biological evaluation as breast cancer radiopharmaceuticals, is reported. The Re complexes displayed under the fluorescence microscope clear uptake by the sensitive to the 2-(4′-aminophenyl)benzothiazole pharmacophore breast cancer cell lines MCF-7 and T47D, while uptake by less sensitive lines and by normal fibroblasts was much weaker. In accordance, uptake of the corresponding radioactive 99mTc complexes was clearly higher in the breast cancer cell lines MCF-7 and MDA-231 compared to normal fibroblasts. Biodistribution of the 99mTc complexes in SCID mice bearing MCF-7 xenografts showed appreciable tumor uptake. A tumor/muscle ratio of 2.2 was measured for the complex conjugated to 2-(4′-aminophenyl)benzothiazole that led to successful tumor imaging. The results render the 2-(4′-aminophenyl)benzothiazole complexes potential candidates for imaging (99mTc) and targeted radiotherapy (188Re) of breast cancer