Chemical and biological studies of Re(I)/Tc(I) thiosemicarbazonate complexes relevant for the design of radiopharmaceuticals

Five thiosemicarbazones (H2Ln) derived from 4,6-diacetylresorcinol (n = 1-4) and salicylaldehyde (n = 5) have been synthesized and spectroscopically characterized. Single crystal X-ray diffraction studies on some of them show that the molecular structure is dominated by intramolecular hydrogen bonds involving the O(1)-H group of the resorcinol/salicylaldehyde group and the azomethinic nitrogen atom and sulfur atom of the thiosemicarbazone arm. All of the ligands react with fac-[ReBr(CO)(3)(CH3CN)(2)] in the presence of NEt3 to form the stable anionic complexes [NHEt3] [fac-[Re(L-n)(CO)(3)] (1-5). The thiosemicarbazonate ligand, as suggested by spectroscopic data and confirmed by X-ray diffraction, acts as a tridentate S,N,O system. The complexes are stable in solution for weeks, although other dimeric species were also detected by X-ray diffraction analysis. The reaction of fac-[99(m)Tc(CO)(3)(H2O)(3)](+) with the appropriate ligand at 100 degrees C for 30 min yielded the complexes [fac-[Tc-99m (L-n)(CO)(3)](-) (Tc1-Tc5). The radiochemical yield and purity were determined by HPLC and their chemical identity was ascertained by comparing their radiochromatogram with the chromatogram of the rhenium congeners (1-5). The results of biodistribution studies in mice on the five technetium compounds showed rapid blood clearance and fast liver uptake that slowly cleared into the intestines, a finding that indicates the hepatobiliary tract as the major excretory pathway. HPLC analysis of urine and blood serum samples from mice injected with the Tc-99m complexes confirmed their in vivo stability since the predominant radiochemical species had the same retention time as the corresponding injected compound.