title: 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, 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-N4-methylthiosemicarbazone (CH3C[=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.
authors.affiliation: Department of Chemistry, Illinois State University, Normal, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Ackerman
authors.forename: D X
authors.initials: DX
authors.lastname: West
authors.forename: C J
authors.initials: CJ
authors.lastname: Mathias
authors.forename: M A
authors.initials: MA
authors.lastname: Green
mesh_terms: D000818:Animals; D003301:Copper Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D006801:Humans; D007275:Injections, Intravenous; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D003301:Copper Radioisotopes; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones