Synthesis and evaluation of copper radiopharmaceuticals with mixed bis(thiosemicarbazone) ligands

Four "mixed" bis(thiosemicarbazone) derivatives of pyruvaldehyde were synthesized that incorporate two dissimilar thiosemicarbazone functions. The corresponding [Cu-67]copper(II) complexes were prepared and evaluated as possible copper radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands, CH3C[=NNHC(S)NHMe]CH[=NNHC(S)NHEt] (1), CH3C[=NNHC(S)NHMe]CH[=NNHC(S)NEt2] (2), CH3C[=NNHC(S)NHMe]CH[=NNHC(S)-cyclo-N(CH2)(5)] (3), and CH3C [=NNHC(S)NHMe]CH[=NNHC(S)-cyclo-N(CH2)(6)] (4), were obtained by reaction of the appropriate thiosemicarbazide derivative with pyruvaldehyde-2-N-4-methylthiosemicarbazone (CH3C[=NNHC(S) NHMe]CHO). The Cu-67-labeled copper(II) complexes of ligands 1-4 were prepared and screened in a rat model to assess the potential of each chelate as a Cu-62-radiopharmaceutical for imaging with positron emission tomography. The Cu-67-complexes of ligands 1-4 exhibit significant uptake into the brain and heart 1 min following intravenous administration to rats. For the Cu-67-complexes of ligands 2, 3, and 4, the cerebral and myocardial uptake of Cu-67 is two-to-threefold lower at 2 h than at 1 min postinjection, due to significant biological clearance of these Cu-67-chelates. However, the Cu-67-complex of 1 affords cerebral and myocardial uptake and retention comparable to that of [Cu-67]Cu-PTSM in this model. Although the kinetics of this new agent appear attractive, ultrafiltration studies using solutions of dog and human serum albumin reveal that the Cu-67-complex of ligand 1, like Cu-PTSM, interacts more strongly with human albumin than dog albumin. Thus, this new agent would appear to offer no advantage over Cu-PTSM as a Cu-62-labeled tracer for evaluation of regional tissue perfusion. (C) 1999 Elsevier Science Inc. All rights reserved.