Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry
Due to its 4 carbonic acid groups being available for bioconjugation, the cyclen tetraphosphinate chelator DOTPI, 1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetrakis[methylene(2-carboxyethylphosphinic acid)], represents an ideal scaffold for synthesis of tetrameric bioconjugates for labeling with radi...
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ftdoajarticles:oai:doaj.org/article:01e301c7310b43c084527984964dfba2 2023-05-15T15:52:57+02:00 Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry Alexander Wurzer Adrienn Vágner Dávid Horváth Flóra Fellegi Hans-Jürgen Wester Ferenc K. Kálmán Johannes Notni 2018-04-01T00:00:00Z https://doi.org/10.3389/fchem.2018.00107 https://doaj.org/article/01e301c7310b43c084527984964dfba2 EN eng Frontiers Media S.A. http://journal.frontiersin.org/article/10.3389/fchem.2018.00107/full https://doaj.org/toc/2296-2646 2296-2646 doi:10.3389/fchem.2018.00107 https://doaj.org/article/01e301c7310b43c084527984964dfba2 Frontiers in Chemistry, Vol 6 (2018) Huisgen-reaction potentiometry spectrophotometry phosphinate radiopharmaceuticals endoradiotherapy Chemistry QD1-999 article 2018 ftdoajarticles https://doi.org/10.3389/fchem.2018.00107 2023-01-08T01:37:13Z Due to its 4 carbonic acid groups being available for bioconjugation, the cyclen tetraphosphinate chelator DOTPI, 1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetrakis[methylene(2-carboxyethylphosphinic acid)], represents an ideal scaffold for synthesis of tetrameric bioconjugates for labeling with radiolanthanides, to be applied as endoradiotherapeuticals. We optimized a protocol for bio-orthogonal DOTPI conjugation via Cu(I)-catalyzed Huisgen-cycloaddition of terminal azides and alkynes (CuAAC), based on the building block DOTPI(azide)4. A detailed investigation of kinetic properties of Cu(II)-DOTPI complexes aimed at optimization of removal of DOTPI-bound copper by transchelation. Protonation and equilibrium properties of Ca(II)-, Zn(II), and Cu(II)-complexes of DOTPI and its tetra-cyclohexylamide DOTPI(Chx)4 (a model for DOTPI conjugates) as well as kinetic inertness (transchelation challenge in the presence of 20 to 40-fold excess of EDTA) were investigated by pH-potentiometry and spectrophotometry. Similar stability constants of CaII-, ZnII, and CuII-complexes of DOTPI (logK(CaL) = 8.65, logK(ZnL = 15.40, logK(CuL) = 20.30) and DOTPI(Chx)4 (logK(CaL) = 8.99, logK(ZnL) = 15.13, logK(CuL) = 20.42) were found. Transchelation of Cu(II)-complexes occurs via proton-assisted dissociation, whereafter released Cu(II) is scavenged by EDTA. The corresponding dissociation rates [kd = 25 × 10−7 and 5 × 10−7 s−1 for Cu(DOTPI) and Cu(DOTPI(Chx)4), respectively, at pH 4 and 298 K] indicate that conjugation increases the kinetic inertness by a factor of 5. However, demetallation is completed within 4.5 and 7.2 h at pH 2 and 25°C, respectively, indicating that Cu(II) removal after formation of CuAAC can be achieved in an uncomplicated manner by addition of excess H4EDTA. For proof-of-principle, tetrameric DOTPI conjugates of the prostate-specific membrane antigen (PSMA) targeting motif Lys-urea-Glu (KuE) were synthesized via CuAAC as well as dibenzo-azacyclooctine (DBCO) based, strain-promoted click chemistry (SPAAC), which ... Article in Journal/Newspaper Carbonic acid Directory of Open Access Journals: DOAJ Articles Frontiers in Chemistry 6 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
topic |
Huisgen-reaction potentiometry spectrophotometry phosphinate radiopharmaceuticals endoradiotherapy Chemistry QD1-999 |
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Huisgen-reaction potentiometry spectrophotometry phosphinate radiopharmaceuticals endoradiotherapy Chemistry QD1-999 Alexander Wurzer Adrienn Vágner Dávid Horváth Flóra Fellegi Hans-Jürgen Wester Ferenc K. Kálmán Johannes Notni Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry |
topic_facet |
Huisgen-reaction potentiometry spectrophotometry phosphinate radiopharmaceuticals endoradiotherapy Chemistry QD1-999 |
description |
Due to its 4 carbonic acid groups being available for bioconjugation, the cyclen tetraphosphinate chelator DOTPI, 1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetrakis[methylene(2-carboxyethylphosphinic acid)], represents an ideal scaffold for synthesis of tetrameric bioconjugates for labeling with radiolanthanides, to be applied as endoradiotherapeuticals. We optimized a protocol for bio-orthogonal DOTPI conjugation via Cu(I)-catalyzed Huisgen-cycloaddition of terminal azides and alkynes (CuAAC), based on the building block DOTPI(azide)4. A detailed investigation of kinetic properties of Cu(II)-DOTPI complexes aimed at optimization of removal of DOTPI-bound copper by transchelation. Protonation and equilibrium properties of Ca(II)-, Zn(II), and Cu(II)-complexes of DOTPI and its tetra-cyclohexylamide DOTPI(Chx)4 (a model for DOTPI conjugates) as well as kinetic inertness (transchelation challenge in the presence of 20 to 40-fold excess of EDTA) were investigated by pH-potentiometry and spectrophotometry. Similar stability constants of CaII-, ZnII, and CuII-complexes of DOTPI (logK(CaL) = 8.65, logK(ZnL = 15.40, logK(CuL) = 20.30) and DOTPI(Chx)4 (logK(CaL) = 8.99, logK(ZnL) = 15.13, logK(CuL) = 20.42) were found. Transchelation of Cu(II)-complexes occurs via proton-assisted dissociation, whereafter released Cu(II) is scavenged by EDTA. The corresponding dissociation rates [kd = 25 × 10−7 and 5 × 10−7 s−1 for Cu(DOTPI) and Cu(DOTPI(Chx)4), respectively, at pH 4 and 298 K] indicate that conjugation increases the kinetic inertness by a factor of 5. However, demetallation is completed within 4.5 and 7.2 h at pH 2 and 25°C, respectively, indicating that Cu(II) removal after formation of CuAAC can be achieved in an uncomplicated manner by addition of excess H4EDTA. For proof-of-principle, tetrameric DOTPI conjugates of the prostate-specific membrane antigen (PSMA) targeting motif Lys-urea-Glu (KuE) were synthesized via CuAAC as well as dibenzo-azacyclooctine (DBCO) based, strain-promoted click chemistry (SPAAC), which ... |
format |
Article in Journal/Newspaper |
author |
Alexander Wurzer Adrienn Vágner Dávid Horváth Flóra Fellegi Hans-Jürgen Wester Ferenc K. Kálmán Johannes Notni |
author_facet |
Alexander Wurzer Adrienn Vágner Dávid Horváth Flóra Fellegi Hans-Jürgen Wester Ferenc K. Kálmán Johannes Notni |
author_sort |
Alexander Wurzer |
title |
Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry |
title_short |
Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry |
title_full |
Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry |
title_fullStr |
Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry |
title_full_unstemmed |
Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry |
title_sort |
synthesis of symmetrical tetrameric conjugates of the radiolanthanide chelator dotpi for application in endoradiotherapy by means of click chemistry |
publisher |
Frontiers Media S.A. |
publishDate |
2018 |
url |
https://doi.org/10.3389/fchem.2018.00107 https://doaj.org/article/01e301c7310b43c084527984964dfba2 |
genre |
Carbonic acid |
genre_facet |
Carbonic acid |
op_source |
Frontiers in Chemistry, Vol 6 (2018) |
op_relation |
http://journal.frontiersin.org/article/10.3389/fchem.2018.00107/full https://doaj.org/toc/2296-2646 2296-2646 doi:10.3389/fchem.2018.00107 https://doaj.org/article/01e301c7310b43c084527984964dfba2 |
op_doi |
https://doi.org/10.3389/fchem.2018.00107 |
container_title |
Frontiers in Chemistry |
container_volume |
6 |
_version_ |
1766388033544781824 |