ИСТИНА

Nowadays alpha-emitting bismuth isotopes are very perspective for targeted alpha therapy. This work is focused on the complex formation of Bi3+ cations with series of new pyridine-containing amide azacrown ethers with or without pendant functional groups including evaluation of leading complex for in vitro serum stability and in vivo behavior. All studied azacrown-ethers form complexes with Bi3+ which stability constants linearly correlate with ligand’s affinity to proton. Ligands without carboxylic arms form two types of complexes with M:L=1:1 and 1:2. Upon pH increasing for all ligands except L formation of LM(OH)n species was observed. Ligand L possessing three carboxylic groups forms the most stable complex with Bi3+ (logK=21.3±0.2) through the studied ligands. According to DFT calculations Bi3+ is located in the macrocyclic cavity holding by two carboxylic arms on one side and one from the other. The calculated Interatomic distances are in agreement with EXAFS measurement of the complex. Complex BiL demonstrates stability in 100 times volume excess of fetal bovine serum: during 3 h 50% dissociated vs BiEDTA complex >95% after 2 h. Moreover biodistribution in the normal BALB/c mice showed 2 times faster clearance and twice lower accumulation in all organs compared to BiEDTA. This indirectly confirms in vivo stability of the complex. The results of in vitro serum stability and in vivo biodistribution studies suggest that this ligand can be promising as bifunctional chelator for the preparation of radiopharmaceutical with 213Bi.