Lj. Ackerman et al., Synthesis and evaluation of copper radiopharmaceuticals with mixed bis(thiosemicarbazone) ligands, NUCL MED BI, 26(5), 1999, pp. 551-554
Four "mixed" bis(thiosemicarbazone) derivatives of pyruvaldehyde were synth
esized that incorporate two dissimilar thiosemicarbazone functions. The cor
responding [Cu-67]copper(II) complexes were prepared and evaluated as possi
ble copper radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemi
carbazone) ligands, CH3C[=NNHC(S)NHMe]CH[=NNHC(S)NHEt] (1), CH3C[=NNHC(S)NH
Me]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 pyruvaldehyd
e-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 mo
del to assess the potential of each chelate as a Cu-62-radiopharmaceutical
for imaging with positron emission tomography. The Cu-67-complexes of ligan
ds 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 lo
wer at 2 h than at 1 min postinjection, due to significant biological clear
ance of these Cu-67-chelates. However, the Cu-67-complex of 1 affords cereb
ral and myocardial uptake and retention comparable to that of [Cu-67]Cu-PTS
M in this model. Although the kinetics of this new agent appear attractive,
ultrafiltration studies using solutions of dog and human serum albumin rev
eal that the Cu-67-complex of ligand 1, like Cu-PTSM, interacts more strong
ly with human albumin than dog albumin. Thus, this new agent would appear t
o 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 res
erved.