Mixed bis(thiosemicarbazone) ligands for the preparation of copper radiopharmaceuticals

Synthesis and evaluation of tetradentate ligands containing two dissimilar thiosemicarbazone functions

John K. Lim, Carla J. Mathias, Mark Green

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31 Citations (Scopus)

Abstract

A series of four 'mixed' bis(thiosemicarbazone) keto aldehyde derivatives containing dissimilar thiosemicarbazone functions were synthesized and evaluated as ligands for preparation of radiocopper-labeled radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands CH3C[=NNHC(S)NH2]CH[=NNHC(S)NHMe] (4a), CH3C[=NNHC(S)NHMe]- CH[=NNHC(S)NH2] (4b), CH3C[=NNHC(S)NH2]CH[=NNHC(S)NMe2] (4c), and CH3C[=NNHC-(S)NHMe]CH[=NNHC(S)NMe2] (4d) were obtained by reaction of thiosemicarbazide, N4-methylthiosemicarbazide, or N4,N4- dimethylthiosemicarbazide with pyruvaldehyde 2-thiosemicarbazones that had been generated by oxidative cleavage of the appropriate pyruvic aldehyde dimethyl acetal 2-thiosemicarbazone. The 67Cu-labeled complexes of ligands 4a-d 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. In the rat model the 67Cu complexes of ligands 4a-d exhibit significant uptake into the brain and heart after intravenous injection, following trends similar to those previously reported for the related bis(thiosemicarbazone) complexes, Cu-PTS, Cu-PTSM, and Cu-PTSM2 (derived from pyruvaldehyde bis(thiosemicarbazone), pyruvaldehyde bis(N4- methylthiosemicarbazone), and pyruvaldehyde bis(N4,N4- dimethylthiosemicarbazone), respectively). Ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu complexes of ligands 4a-d, like the Cu(II) complex of pyruvaldehyde bis(N4- methylthiosemicarbazone), interact more strongly with human albumin than dog albumin.

Original languageEnglish (US)
Pages (from-to)132-136
Number of pages5
JournalJournal of Medicinal Chemistry
Volume40
Issue number1
DOIs
StatePublished - Jan 3 1997
Externally publishedYes

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Thiosemicarbazones
Pyruvaldehyde
Radiopharmaceuticals
Copper
Ligands
Rats
Albumins
Dogs
Positron emission tomography
Ultrafiltration
Aldehydes
Serum Albumin
Intravenous Injections
Positron-Emission Tomography
Brain
Derivatives
Imaging techniques

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{ff1ffa069c704812a3c8931344d14409,
title = "Mixed bis(thiosemicarbazone) ligands for the preparation of copper radiopharmaceuticals: Synthesis and evaluation of tetradentate ligands containing two dissimilar thiosemicarbazone functions",
abstract = "A series of four 'mixed' bis(thiosemicarbazone) keto aldehyde derivatives containing dissimilar thiosemicarbazone functions were synthesized and evaluated as ligands for preparation of radiocopper-labeled radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands CH3C[=NNHC(S)NH2]CH[=NNHC(S)NHMe] (4a), CH3C[=NNHC(S)NHMe]- CH[=NNHC(S)NH2] (4b), CH3C[=NNHC(S)NH2]CH[=NNHC(S)NMe2] (4c), and CH3C[=NNHC-(S)NHMe]CH[=NNHC(S)NMe2] (4d) were obtained by reaction of thiosemicarbazide, N4-methylthiosemicarbazide, or N4,N4- dimethylthiosemicarbazide with pyruvaldehyde 2-thiosemicarbazones that had been generated by oxidative cleavage of the appropriate pyruvic aldehyde dimethyl acetal 2-thiosemicarbazone. The 67Cu-labeled complexes of ligands 4a-d 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. In the rat model the 67Cu complexes of ligands 4a-d exhibit significant uptake into the brain and heart after intravenous injection, following trends similar to those previously reported for the related bis(thiosemicarbazone) complexes, Cu-PTS, Cu-PTSM, and Cu-PTSM2 (derived from pyruvaldehyde bis(thiosemicarbazone), pyruvaldehyde bis(N4- methylthiosemicarbazone), and pyruvaldehyde bis(N4,N4- dimethylthiosemicarbazone), respectively). Ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu complexes of ligands 4a-d, like the Cu(II) complex of pyruvaldehyde bis(N4- methylthiosemicarbazone), interact more strongly with human albumin than dog albumin.",
author = "Lim, {John K.} and Mathias, {Carla J.} and Mark Green",
year = "1997",
month = "1",
day = "3",
doi = "10.1021/jm9605703",
language = "English (US)",
volume = "40",
pages = "132--136",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "1",

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TY - JOUR

T1 - Mixed bis(thiosemicarbazone) ligands for the preparation of copper radiopharmaceuticals

T2 - Synthesis and evaluation of tetradentate ligands containing two dissimilar thiosemicarbazone functions

AU - Lim, John K.

AU - Mathias, Carla J.

AU - Green, Mark

PY - 1997/1/3

Y1 - 1997/1/3

N2 - A series of four 'mixed' bis(thiosemicarbazone) keto aldehyde derivatives containing dissimilar thiosemicarbazone functions were synthesized and evaluated as ligands for preparation of radiocopper-labeled radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands CH3C[=NNHC(S)NH2]CH[=NNHC(S)NHMe] (4a), CH3C[=NNHC(S)NHMe]- CH[=NNHC(S)NH2] (4b), CH3C[=NNHC(S)NH2]CH[=NNHC(S)NMe2] (4c), and CH3C[=NNHC-(S)NHMe]CH[=NNHC(S)NMe2] (4d) were obtained by reaction of thiosemicarbazide, N4-methylthiosemicarbazide, or N4,N4- dimethylthiosemicarbazide with pyruvaldehyde 2-thiosemicarbazones that had been generated by oxidative cleavage of the appropriate pyruvic aldehyde dimethyl acetal 2-thiosemicarbazone. The 67Cu-labeled complexes of ligands 4a-d 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. In the rat model the 67Cu complexes of ligands 4a-d exhibit significant uptake into the brain and heart after intravenous injection, following trends similar to those previously reported for the related bis(thiosemicarbazone) complexes, Cu-PTS, Cu-PTSM, and Cu-PTSM2 (derived from pyruvaldehyde bis(thiosemicarbazone), pyruvaldehyde bis(N4- methylthiosemicarbazone), and pyruvaldehyde bis(N4,N4- dimethylthiosemicarbazone), respectively). Ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu complexes of ligands 4a-d, like the Cu(II) complex of pyruvaldehyde bis(N4- methylthiosemicarbazone), interact more strongly with human albumin than dog albumin.

AB - A series of four 'mixed' bis(thiosemicarbazone) keto aldehyde derivatives containing dissimilar thiosemicarbazone functions were synthesized and evaluated as ligands for preparation of radiocopper-labeled radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands CH3C[=NNHC(S)NH2]CH[=NNHC(S)NHMe] (4a), CH3C[=NNHC(S)NHMe]- CH[=NNHC(S)NH2] (4b), CH3C[=NNHC(S)NH2]CH[=NNHC(S)NMe2] (4c), and CH3C[=NNHC-(S)NHMe]CH[=NNHC(S)NMe2] (4d) were obtained by reaction of thiosemicarbazide, N4-methylthiosemicarbazide, or N4,N4- dimethylthiosemicarbazide with pyruvaldehyde 2-thiosemicarbazones that had been generated by oxidative cleavage of the appropriate pyruvic aldehyde dimethyl acetal 2-thiosemicarbazone. The 67Cu-labeled complexes of ligands 4a-d 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. In the rat model the 67Cu complexes of ligands 4a-d exhibit significant uptake into the brain and heart after intravenous injection, following trends similar to those previously reported for the related bis(thiosemicarbazone) complexes, Cu-PTS, Cu-PTSM, and Cu-PTSM2 (derived from pyruvaldehyde bis(thiosemicarbazone), pyruvaldehyde bis(N4- methylthiosemicarbazone), and pyruvaldehyde bis(N4,N4- dimethylthiosemicarbazone), respectively). Ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu complexes of ligands 4a-d, like the Cu(II) complex of pyruvaldehyde bis(N4- methylthiosemicarbazone), interact more strongly with human albumin than dog albumin.

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