Mixed bis(thiosemicarbazone) ligands for the preparation of copper radiopharmaceuticals: synthesis and evaluation of tetradentate ligands containing two dissimilar thiosemicarbazone functions.

Abstract

A series of four "mixed" bis(thiosemicarbazone) keto aldehyde derivatives containing dissimilar thiosemicarbazone functions were synthesized and evaluated as ligands for preparation of radiocopper-labeled radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands CH3C[=NNHC(S)NH2]CH[=NNHC(S)NHMe] (4a), CH3C[=NNHC(S)NHMe]-CH[=NNHC(S)NH2] (4b), CH3C[=NNHC(S)NH2]CH[=NNHC(S)NMe2] (4c), and CH3C[=NNHC-(S)NHMe]CH[=NNHC(S)NMe2] (4d) were obtained by reaction of thiosemicarbazide, N4-methylthiosemicarbazide, or N4,N4-dimethylthiosemicarbazide with pyruvaldehyde 2-thiosemicarbazones that had been generated by oxidative cleavage of the appropriate pyruvic aldehyde dimethyl acetal 2-thiosemicarbazone. The 67Cu-labeled complexes of ligands 4a-d were prepared and screened in a rat model to assess the potential of each chelate as a 62Cu radiopharmaceutical for imaging with positron emission tomography. In the rat model the 67Cu complexes of ligands 4a-d exhibit significant uptake into the brain and heart after intravenous injection, following trends similar to those previously reported for the related bis(thiosemicarbazone) complexes, Cu-PTS, Cu-PTSM, and Cu-PTSM2 (derived from pyruvaldehyde bis(thiosemicarbazone), pyruvaldehyde bis(N4-methylthiosemicarbazone), and pyruvaldehyde bis(N4,N4-dimethylthiosemicarbazone), respectively). Ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu complexes of ligands 4a-d, like the Cu(II) complex of pyruvaldehyde bis(N4-methylthiosemicarbazone), interact more strongly with human albumin than dog albumin.