MIXED BIS(THIOSEMICARBAZONE) LIGANDS FOR THE PREPARATION OF COPPER RADIOPHARMACEUTICALS - SYNTHESIS AND EVALUATION OF TETRADENTATE LIGANDS CONTAINING 2 DISSIMILAR THIOSEMICARBAZONE FUNCTIONS

A series of four ''mixed'' bis(thiosemicarbazone) keto aldehyde deriva tives containing dissimilar thiosemicarbazone functions were synthesiz ed and evaluated as ligands for preparation of radiocopper-labeled rad iopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone ) Ligands CH3C[=NNHC(S)NH2]CH[=NNHC(S)NHMe] (4a), CH3C[-NNHC(S)NHMe]-C H[=NNHC(S)NH2] (4b), CH3[=NNHC(S)NH2]CH[=NNHC(S)NMe(2)] (4c), and CH3C [=NNHC(S)NHMe]CH[=NNHC(S)NMe(2)] (4d) were obtained by reaction of thi osemicarbazide, N-4-methylthiosemicarbazide, or N-4,N-4-dimethylthiose micarbazide with pyruvaldehyde 2-thiosemicarbazones that had been gene rated by oxidative cleavage of the appropriate pyruvic aldehyde dimeth yl acetal 2-thiosemicarbazone. The Cu-67-labeled complexes of Ligands 4a-d were prepared and screened in a rat model to assess the potential of each chelate as a Cu-62 radiopharmaceutical for imaging with posit ron emission tomography. In the rat model the Cu-67 complexes of ligan ds 4a-d exhibit significant uptake into the brain and heart after intr avenous injection, following trends similar to those previously report ed for the related bis(thiosemicarbazone) complexes, Cu-PTS, Cu-PTSM, and Cu-PTSM(2) (derived from pyruvaldehyde bis(thiosemicarbazone), pyr uvaldehyde bis(N-4-methylthiosemicarbazone), and pyruvaldehyde bis(N-4 ,N-4-dimethylthiosemicarbazone), respectively). Ultrafiltration studie s using solutions of dog and human serum albumin reveal that the Cu-67 complexes of ligands 4a-d, Like the Cu(II) complex of pyruvaldehyde b is(N-4-methylthiosemicarbazone), interact more strongly with human alb umin than dog albumin.