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Development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes

Hydroxamamide (Ham) is a thiol-free chelating agent that forms technetium-99m ((99m)Tc)-complexes with a metal-to-ligand ratio of 1:2 under moderate reaction conditions. Therefore, Ham-based chelating agents will produce (99m)Tc-labeled compounds with a bivalent targeting scaffold. For their univers...

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Autores principales: Shimizu, Yoichi, Ando, Masato, Iikuni, Shimpei, Watanabe, Hiroyuki, Ono, Masahiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455562/
https://www.ncbi.nlm.nih.gov/pubmed/34548586
http://dx.doi.org/10.1038/s41598-021-98235-x
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author Shimizu, Yoichi
Ando, Masato
Iikuni, Shimpei
Watanabe, Hiroyuki
Ono, Masahiro
author_facet Shimizu, Yoichi
Ando, Masato
Iikuni, Shimpei
Watanabe, Hiroyuki
Ono, Masahiro
author_sort Shimizu, Yoichi
collection PubMed
description Hydroxamamide (Ham) is a thiol-free chelating agent that forms technetium-99m ((99m)Tc)-complexes with a metal-to-ligand ratio of 1:2 under moderate reaction conditions. Therefore, Ham-based chelating agents will produce (99m)Tc-labeled compounds with a bivalent targeting scaffold. For their universal usage, we developed a novel Ham-based bifunctional chelating agent, “Ham-Mal”, with a maleimide group that can easily conjugate with a thiol group, for to preparing (99m)Tc-labeled bivalent ligand probes. Ham-Mal was synthesized by a four-step reaction, and then reacted with cysteine or c(RGDfC) to produce Ham-Cys or Ham-RGD. These precursors were reacted with (99m)TcO(4)(-) for 10 min under room temperature to obtain (99m)Tc-(Ham-Cys)(2) and (99m)Tc -(Ham-RGD)(2). The cellular uptake level of (99m)Tc-(Ham-RGD)(2) by U87MG (high Integrin ɑ(v)β(3) expression) cells was significantly higher than that by PC3 (low Integrin ɑ(v)β(3) expression) cells at 60 min after the incubation, and the uptake was significantly suppressed by pre-treatment for 15 min with excess c(RGDfK) peptide. In the in vivo study with U87MG/PC3 dual xenografted BALB/c-nu mice, the radioactivity of U87MG tumor tissue was significantly higher than that of PC3 tumor tissue at 360 min after the administration of (99m)Tc-(Ham-RGD)(2). These results suggest Ham-Mal may have potential as a bifunctional chelating agent for (99m)Tc-labeled bivalent ligand probes.
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spelling pubmed-84555622021-09-22 Development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes Shimizu, Yoichi Ando, Masato Iikuni, Shimpei Watanabe, Hiroyuki Ono, Masahiro Sci Rep Article Hydroxamamide (Ham) is a thiol-free chelating agent that forms technetium-99m ((99m)Tc)-complexes with a metal-to-ligand ratio of 1:2 under moderate reaction conditions. Therefore, Ham-based chelating agents will produce (99m)Tc-labeled compounds with a bivalent targeting scaffold. For their universal usage, we developed a novel Ham-based bifunctional chelating agent, “Ham-Mal”, with a maleimide group that can easily conjugate with a thiol group, for to preparing (99m)Tc-labeled bivalent ligand probes. Ham-Mal was synthesized by a four-step reaction, and then reacted with cysteine or c(RGDfC) to produce Ham-Cys or Ham-RGD. These precursors were reacted with (99m)TcO(4)(-) for 10 min under room temperature to obtain (99m)Tc-(Ham-Cys)(2) and (99m)Tc -(Ham-RGD)(2). The cellular uptake level of (99m)Tc-(Ham-RGD)(2) by U87MG (high Integrin ɑ(v)β(3) expression) cells was significantly higher than that by PC3 (low Integrin ɑ(v)β(3) expression) cells at 60 min after the incubation, and the uptake was significantly suppressed by pre-treatment for 15 min with excess c(RGDfK) peptide. In the in vivo study with U87MG/PC3 dual xenografted BALB/c-nu mice, the radioactivity of U87MG tumor tissue was significantly higher than that of PC3 tumor tissue at 360 min after the administration of (99m)Tc-(Ham-RGD)(2). These results suggest Ham-Mal may have potential as a bifunctional chelating agent for (99m)Tc-labeled bivalent ligand probes. Nature Publishing Group UK 2021-09-21 /pmc/articles/PMC8455562/ /pubmed/34548586 http://dx.doi.org/10.1038/s41598-021-98235-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Shimizu, Yoichi
Ando, Masato
Iikuni, Shimpei
Watanabe, Hiroyuki
Ono, Masahiro
Development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes
title Development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes
title_full Development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes
title_fullStr Development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes
title_full_unstemmed Development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes
title_short Development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes
title_sort development of a hydroxamamide-based bifunctional chelating agent to prepare technetium-99m-labeled bivalent ligand probes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455562/
https://www.ncbi.nlm.nih.gov/pubmed/34548586
http://dx.doi.org/10.1038/s41598-021-98235-x
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