Effect of the type of N-substituent in the benzo-18-azacrown-6 compound on copper(II) chelation: complexation, radiolabeling, stability in vitro, and biodistribution in vivo.

In this work, we synthesized two new benzo-18-azacrown-6 ethers bearing picolinate and pyridine pendant arms and studied the copper complexes of these ligands, as well as those of an acetate analog. All considered ligands were capable of forming mono- and dinuclear complexes due to their large size and large number of donor sites. Among all forms of complexes, the coordination of cations inside the macrocycle has only been shown for the mononuclear form of the acetate complex, while out-cage coordination has been observed for other forms. Electrochemical studies have shown the instability of the mononuclear form of the complex with the pyridine ligand to the reduction in the range of redox potentials of bioreductants. The stabilities of labeled acetate complexes with "in-cage" coordination of the cation and picolinate with "out-cage" coordination were compared in an excess of serum and superoxide dismutase; while the former turned out to be unstable to transchelation, the latter was stable throughout the experiment. Additional studies in biologically relevant media were performed for the picolinate complex and demonstrated its stability in vitro. The biodistribution of this complex in mice after 6 hours post-injection demonstrates a slow excretion from the body; however, the accumulation is noticeably lower than that of free copper cations.

Photonuclear production of medical radioisotopes 161Tb and 155Tb.

The production possibility of 161Tb and 155Tb by irradiating of natural dysprosium with gamma rays obtained by decelerating an electron beam with an energy of 55 MeV has been demonstrated experimentally. The yield of 161Tb was 14.4 × 103 Bq × µA-1 × h-1 × cm2 × gDy2O3-1. Simultaneously, upon irradiation, 155Dy is formed with the yield of 25 × 103 Bq × µA-1 × h-1 × cm2 × gDy2O3-1, which leads to the formation of 1.6 × 103 Bq × µA-1 × h-1 × cm2 × gDy2O3-1 of 155Tb. It has been shown that the isolation of terbium radioisotopes from tens of mg of dysprosium target can be achieved by extraction chromatography, and final separation yield was 39%. The impurity of 160Tb is 7.3% of the 161Tb activity at EOB.

Specific Cytotoxicity of Targeted 177Lu and 212Pb-Based Radiopharmaceuticals.

Two radiopharmaceutical preparations were developed on the basis of artificial targeted polypeptide ZHER2 specific to HER2/neu tumor marker and radionuclides 177Lu (ZHER2-HSA-chelator-177Lu) or 212Pb (ZHER2-HSA-chelator-212Pb). The objective was to evaluate in vitro the cytotoxic activity of the targeted radiopharmaceuticals using two cultured human breast cancer cell lines with different expression of HER2/neu: SK-BR3 (high expression of HER2/neu) and MCF-7 (low expression of HER2/neu). It was shown that the cytotoxic effect of both preparations was significantly higher against the SK-BR-3 cells. The cytotoxicity correlated with the incubation period (it was higher after 72 h than after 24 h) and was significantly more pronounced in comparison with activity of radionuclide salts without a specific ligand. In vivo preclinical study of these pharmaceuticals seems to be very promising in animals with xenografted tumors showing high expression of HER2/neu marker.