Species-dependent binding of copper(II) bis(thiosemicarbazone) radiopharmaceuticals to serum albumin.
Copper-62-labeled pyruvaldehyde bis(N4-methylthiosemicarbazonato)-copper(II) (Cu-PTSM) is a generator-based PET radiopharmaceutical under investigation for use in evaluation of tissue perfusion. Despite promising results from animals, problems have been encountered in the use of 62Cu-PTSM to quantitate myocardial perfusion in humans at high flow rates, possibly due to species-dependent interactions of the tracer with serum albumin.


METHODS
Ultrafiltration and plasma/erythrocyte partitioning studies were performed to assess the protein binding of 67Cu-labeled Cu-PTSM and six related copper(II) bis(thiosemicarbazone) complexes.


RESULTS
These studies reveal significant interspecies variability in the strength of Cu-PTSM binding to serum albumin, with 67Cu-PTSM binding much more strongly to human albumin than to dog albumin. Most of the related Cu(II)-bis(thiosemicarbazone) complexes examined exhibit interspecies variability of albumin binding similar to that observed with Cu-PTSM. Two such complexes, Cu-ETS and Cu-n-PrTS, however, were identified that exhibit no preferential association with human serum albumin.


CONCLUSIONS
Copper-62-PTSM exhibits substantial interspecies variability in the strength of its binding to serum albumin, which appears to explain the problems encountered in using animal data to predict 62Cu-PTSM behavior in humans. The 62Cu-ETS and 62Cu-n-PrTS complexes may be viable alternatives to 62Cu-PTSM for PET studies to evaluate quantitatively myocardial blood flow in humans.
Mathias
C J
CJ
Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907-1333, USA.
Bergmann
S R
SR
Green
M A
MA
D000818:Animals; D003300:Copper / Q000493:pharmacokinetics; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D004285:Dogs; D006321:Heart / Q000000981:diagnostic imaging; D006801:Humans; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D013045:Species Specificity; D013882:Thiosemicarbazones / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014462:Ultrafiltration
D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D012709:Serum Albumin; D013882:Thiosemicarbazones; C052629:copper pyruvaldehyde bis(N(4)-methylthiosemicarbazone) complex; D003300:Copper