ИСТИНА

Polyaminopolycarboxylates are attractive ligands as linkers in radiopharmaceuticals for target delivery of specific radionuclides to the tumor cells. Nowadays beta emitting radionuclides of rare earth elements , i.e. Y-90 and Lu-177, are used as therapeutic agents, Ac-225/ Bi-213, Pb-212/ Bi-212 and Cu-67 are considered as perspective for alpha and beta therapy and Cu-64 is a radionuclide for positron emission tomography. In the present work new data on possibilities of azacrown moieties to complex several tri- and divalent cations are studied. Considered azacrown compounds form complexes with cations within first minutes that confirmed by UV-vis spectroscopy. For ligands’ and complexes’ characterization potentiometric titration and competitive technique were used. Potentiometric titration data were treated using HYPERQUAD software, as competitive processes liquid extraction and precipitation were performed. Azacrown ethers possess different acidity that affects by the presence of carbamide groups, macrocyclic ring size and addition of carboxylic arms or pyridine fragments. It was found that binding of such “hard” cations as Y3+ requires availability of carboxylic groups in ligand but calculated constants (table) are still less than the values required for in vivo applications. The highest values of stability constants were determined for Bi3+ (table). It is bound quantitatively even at pH3. It is shown that L1a and L2a form complexes with Bi3+ with two stoichiometries 1:1 and 1:2. L1b, L1c and L2b form ternary complexes with Bi:L=1:1 and presence of OH- depending on pH. Bi3+ as extremely hydrolysable cation possesses affinity to different ligands as OH- and different polyaminopolycarboxylates, so constants of respective complexes are usually higher than analogous complexes with trivalent REE. Therefore even without carboxylates strong watersoluble complexes with Bi3+ could be formed. Table. Calculated logKML, µ=0.1M NaClO4 M L1 L2 a) X=H b) X=CH2COOH c) X=CH2Py a) X=H b) X=CH2COOH ΣpKa 11.8(2) 15.1(1) 11.4(1) 15.4(1) 22.4(2) Y3+ - 5.5(4) - - 6.9(3) Bi3+ 12.5(1) 16.3(2) 11.8(4) 14.4(1) 21.3(2) Pb2+ - 8.7(1) 4.9(1) 4.9(1) 14.1(1) Cu2+ 8.8(2) 11.2(1) 8.9(1) 10.8(6) 15.8(1) Among studied divalent cations azacrown-ethers demonstrate preference to Cu2+ in comparison to Pb2+. The same tendency as for Bi3+: constants increasing with addition of carboxylic arms and no influence of pyridine pendant groups. It is important to note that all calculated constants correlate with determined acidity constants of ligands (table) and in line with literature data for complexes with other polyaminopolycarboxilates. To evaluate structure of formed complexes time resolved laser induced fluorescence spectroscopy (TRLIFs) on Eu3+ cation as Y3+ and Lu3+ chemical analog was performed. It was shown that despite the presence of larger number of donor atoms in L2b it does not correspond to the higher stability of Y-L2b in comparison with Y-L1b. For both complexes the number of water molecules in Eu3+ environment was determined to be 2.4±0.5. Furthermore the best of considered ligands L2b was tested for cytotoxicity by MTT assay for leukemia cell lines and healthy blood cells. It was shown that for cancer cells LC50=(5±2)·10-4M and for healthy white blood cells LC50=(4±3)·10-3M. Obtained concentrations are suggested not to be ever achieved in the cell during the treatment of disease, so we suppose that pyridine-containing azacrown compounds themselves are not toxic for any cells. This work was supported by RFBR project 16-33-00642.