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

Abstract

Four “mixed” bis(thiosemicarbazone) derivatives of pyruvaldehyde were synthesized that incorporate two dissimilar thiosemicarbazone functions. The corresponding [ 67Cu]copper(II) complexes were prepared and evaluated as possible copper radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands, CH 3C[=NNHC(S)NHMe]CH[=NNHC(S)NHEt] (1), CH 3C[=NNHC(S)NHMe]CH[=NNHC(S)NEt 2] (2), CH 3C[=NNHC(S)NHMe]CH[=NNHC(S)- cyclo-N(CH 2) 5] (3), and CH 3C[=NNHC(S)NHMe]CH[=NNHC(S)- cyclo-N(CH 2) 6] (4), were obtained by reaction of the appropriate thiosemicarbazide derivative with pyruvaldehyde-2- N 4 -methylthiosemicarbazone (CH 3C[=NNHC(S)NHMe]CHO). The 67Cu-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 62Cu-radiopharmaceutical for imaging with positron emission tomography. The 67Cu-complexes of ligands 1–4 exhibit significant uptake into the brain and heart 1 min following intravenous administration to rats. For the 67Cu-complexes of ligands 2, 3, and 4, the cerebral and myocardial uptake of 67Cu is two-to-threefold lower at 2 h than at 1 min postinjection, due to significant biological clearance of these 67Cu-chelates. However, the 67Cu-complex of 1 affords cerebral and myocardial uptake and retention comparable to that of [ 67Cu]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 67Cu-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 62Cu-labeled tracer for evaluation of regional tissue perfusion.