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(64)Cu-Labeled Somatostatin Analogues Conjugated with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted Click Chemistry for PET Imaging: In silico through in Vivo Studies
[Image: see text] Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chela...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261236/ https://www.ncbi.nlm.nih.gov/pubmed/24983404 http://dx.doi.org/10.1021/jm500416f |
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author | Cai, Zhengxin Ouyang, Qin Zeng, Dexing Nguyen, Kim N. Modi, Jalpa Wang, Lirong White, Alexander G. Rogers, Buck E. Xie, Xiang-Qun Anderson, Carolyn J. |
author_facet | Cai, Zhengxin Ouyang, Qin Zeng, Dexing Nguyen, Kim N. Modi, Jalpa Wang, Lirong White, Alexander G. Rogers, Buck E. Xie, Xiang-Qun Anderson, Carolyn J. |
author_sort | Cai, Zhengxin |
collection | PubMed |
description | [Image: see text] Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr(3)-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P–DBCO–Y3-TATE (AP) and CB-TE1K1P–PEG4–DBCO–Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with K(d) values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues. |
format | Online Article Text |
id | pubmed-4261236 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-42612362014-12-10 (64)Cu-Labeled Somatostatin Analogues Conjugated with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted Click Chemistry for PET Imaging: In silico through in Vivo Studies Cai, Zhengxin Ouyang, Qin Zeng, Dexing Nguyen, Kim N. Modi, Jalpa Wang, Lirong White, Alexander G. Rogers, Buck E. Xie, Xiang-Qun Anderson, Carolyn J. J Med Chem [Image: see text] Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr(3)-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P–DBCO–Y3-TATE (AP) and CB-TE1K1P–PEG4–DBCO–Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with K(d) values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues. American Chemical Society 2014-07-01 2014-07-24 /pmc/articles/PMC4261236/ /pubmed/24983404 http://dx.doi.org/10.1021/jm500416f Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Cai, Zhengxin Ouyang, Qin Zeng, Dexing Nguyen, Kim N. Modi, Jalpa Wang, Lirong White, Alexander G. Rogers, Buck E. Xie, Xiang-Qun Anderson, Carolyn J. (64)Cu-Labeled Somatostatin Analogues Conjugated with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted Click Chemistry for PET Imaging: In silico through in Vivo Studies |
title | (64)Cu-Labeled Somatostatin
Analogues Conjugated
with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted
Click Chemistry for PET Imaging: In silico through in Vivo Studies |
title_full | (64)Cu-Labeled Somatostatin
Analogues Conjugated
with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted
Click Chemistry for PET Imaging: In silico through in Vivo Studies |
title_fullStr | (64)Cu-Labeled Somatostatin
Analogues Conjugated
with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted
Click Chemistry for PET Imaging: In silico through in Vivo Studies |
title_full_unstemmed | (64)Cu-Labeled Somatostatin
Analogues Conjugated
with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted
Click Chemistry for PET Imaging: In silico through in Vivo Studies |
title_short | (64)Cu-Labeled Somatostatin
Analogues Conjugated
with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted
Click Chemistry for PET Imaging: In silico through in Vivo Studies |
title_sort | (64)cu-labeled somatostatin
analogues conjugated
with cross-bridged phosphonate-based chelators via strain-promoted
click chemistry for pet imaging: in silico through in vivo studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261236/ https://www.ncbi.nlm.nih.gov/pubmed/24983404 http://dx.doi.org/10.1021/jm500416f |
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