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[(18)F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4
Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [(68)Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical p...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514812/ https://www.ncbi.nlm.nih.gov/pubmed/31022852 http://dx.doi.org/10.3390/molecules24081612 |
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author | Amor-Coarasa, Alejandro Kelly, James M. Singh, Pradeep K. Ponnala, Shashikanth Nikolopoulou, Anastasia Williams, Clarence Vedvyas, Yogindra Jin, Moonsoo M. Warren, J. David Babich, John W. |
author_facet | Amor-Coarasa, Alejandro Kelly, James M. Singh, Pradeep K. Ponnala, Shashikanth Nikolopoulou, Anastasia Williams, Clarence Vedvyas, Yogindra Jin, Moonsoo M. Warren, J. David Babich, John W. |
author_sort | Amor-Coarasa, Alejandro |
collection | PubMed |
description | Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [(68)Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of (68)Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [(18)F]RPS-534 (7.2 ± 0.3 %ID/g) and [(18)F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [(18)F]RPS-547, and especially [(18)F]RPS-534, are promising (18)F-labeled candidates for imaging CXCR4 expression. |
format | Online Article Text |
id | pubmed-6514812 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-65148122019-05-30 [(18)F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4 Amor-Coarasa, Alejandro Kelly, James M. Singh, Pradeep K. Ponnala, Shashikanth Nikolopoulou, Anastasia Williams, Clarence Vedvyas, Yogindra Jin, Moonsoo M. Warren, J. David Babich, John W. Molecules Article Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [(68)Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of (68)Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [(18)F]RPS-534 (7.2 ± 0.3 %ID/g) and [(18)F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [(18)F]RPS-547, and especially [(18)F]RPS-534, are promising (18)F-labeled candidates for imaging CXCR4 expression. MDPI 2019-04-24 /pmc/articles/PMC6514812/ /pubmed/31022852 http://dx.doi.org/10.3390/molecules24081612 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Amor-Coarasa, Alejandro Kelly, James M. Singh, Pradeep K. Ponnala, Shashikanth Nikolopoulou, Anastasia Williams, Clarence Vedvyas, Yogindra Jin, Moonsoo M. Warren, J. David Babich, John W. [(18)F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4 |
title | [(18)F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4 |
title_full | [(18)F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4 |
title_fullStr | [(18)F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4 |
title_full_unstemmed | [(18)F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4 |
title_short | [(18)F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4 |
title_sort | [(18)f]fluoroethyltriazolyl monocyclam derivatives as imaging probes for the chemokine receptor cxcr4 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514812/ https://www.ncbi.nlm.nih.gov/pubmed/31022852 http://dx.doi.org/10.3390/molecules24081612 |
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