Synthesis, characterization and biological evaluation of 99mTc/Re–tricarbonyl quinolone complexes

Abstract

New rhenium(I) tricarbonyl complexes with the quinolone antimicrobial agents oxolinic acid (Hoxo) and enrofloxacin (Herx) and containing methanol, triphenylphosphine (PPh3) or imidazole (im) as unidentate co-ligands, were synthesized and characterized. The crystal structure of complex [Re(CO)3(oxo)(PPh3)]∙0.5MeOH was determined by X–ray crystallography. The deprotonated quinolone ligands are bound bidentately to rhenium(I) ion through the pyridone oxygen and a carboxylate oxygen. The binding of the rhenium complexes to calf-thymus DNA (CT DNA) was monitored by UV spectroscopy, viscosity measurements and competitive studies with ethidium bromide; intercalation was suggested as the most possible mode and the DNA-binding constants of the complexes were calculated. The rhenium complex [Re(CO)3(erx)(im)] was assayed for its topoisomerase IIα inhibition activity and was found to be active at 100μM concentration. The interaction of the rhenium complexes with human or bovine serum albumin was investigated by fluorescence emission spectroscopy (through the tryptophan quenching) and the corresponding binding constants were determined. The tracer complex [99mTc(CO)3(erx)(im)] was synthesized and identified by comparative HPLC analysis with the rhenium analog. The 99mTc complex was found to be stable in solution. Upon injection in healthy mice, fast tissue clearance of the 99mTc complex was observed, while both renal and hepatobiliary excretion took place. Preliminary studies in human K-562 erythroleukemia cells showed cellular uptake of the 99mTc tracer with distribution primarily in the cytoplasm and the mitochondria and less in the nucleus. These preliminary results indicate that the quinolone 99mTc/Re complexes show promise to be further evaluated as imaging or therapeutic agents.