[18F]fluoroethyltriazolyl monocyclam derivatives as imaging probes for the chemokine receptor CXCR4

Alejandro Amor-Coarasa, James M. Kelly, Pradeep K. Singh, Shashikanth Ponnala, Anastasia Nikolopoulou, Clarence Williams, Yogindra Vedvyas, Moonsoo M. Jin, J. David Warren, John W. Babich

Research output: Contribution to journalArticle

Abstract

Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. 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 [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]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, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.

Original languageEnglish (US)
Article number1612
JournalMolecules
Volume24
Issue number8
DOIs
StatePublished - Apr 24 2019

Fingerprint

Positron emission tomography
Molecular modeling
Chemokine Receptors
Drug Discovery
Positron-Emission Tomography
Tumors
tumors
Derivatives
Imaging techniques
probes
Neoplasms
affinity
Bearings (structural)
cells
Click Chemistry
Ligands
ligands
scoring
Fluorine
muscles

Keywords

  • Chemokine receptor
  • CXCR4
  • Drug discovery
  • Molecular modeling
  • Positron emission tomography

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Amor-Coarasa, A., Kelly, J. M., Singh, P. K., Ponnala, S., Nikolopoulou, A., Williams, C., ... Babich, J. W. (2019). [18F]fluoroethyltriazolyl monocyclam derivatives as imaging probes for the chemokine receptor CXCR4. Molecules, 24(8), [1612]. https://doi.org/10.3390/molecules24081612

[18F]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.; David Warren, J.; Babich, John W.

In: Molecules, Vol. 24, No. 8, 1612, 24.04.2019.

Research output: Contribution to journalArticle

Amor-Coarasa, A, Kelly, JM, Singh, PK, Ponnala, S, Nikolopoulou, A, Williams, C, Vedvyas, Y, Jin, MM, David Warren, J & Babich, JW 2019, '[18F]fluoroethyltriazolyl monocyclam derivatives as imaging probes for the chemokine receptor CXCR4', Molecules, vol. 24, no. 8, 1612. https://doi.org/10.3390/molecules24081612
Amor-Coarasa, Alejandro ; Kelly, James M. ; Singh, Pradeep K. ; Ponnala, Shashikanth ; Nikolopoulou, Anastasia ; Williams, Clarence ; Vedvyas, Yogindra ; Jin, Moonsoo M. ; David Warren, J. ; Babich, John W. / [18F]fluoroethyltriazolyl monocyclam derivatives as imaging probes for the chemokine receptor CXCR4. In: Molecules. 2019 ; Vol. 24, No. 8.
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abstract = "Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. 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 [18F]RPS-534 (7.2 ± 0.3 {\%}ID/g) and [18F]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, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.",
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AU - Amor-Coarasa, Alejandro

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AU - Ponnala, Shashikanth

AU - Nikolopoulou, Anastasia

AU - Williams, Clarence

AU - Vedvyas, Yogindra

AU - Jin, Moonsoo M.

AU - David Warren, J.

AU - Babich, John W.

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N2 - Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. 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 [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]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, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.

AB - Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. 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 [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]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, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.

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KW - CXCR4

KW - Drug discovery

KW - Molecular modeling

KW - Positron emission tomography

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