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N-[(11)C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs

PURPOSE: Chemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[(11)C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[(11)C]methyl-AMD3465 in...

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Autores principales: Hartimath, S. V., Khayum, M. A., van Waarde, A., Dierckx, R. A. J. O., de Vries, E. F. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498639/
https://www.ncbi.nlm.nih.gov/pubmed/27896627
http://dx.doi.org/10.1007/s11307-016-1028-8
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author Hartimath, S. V.
Khayum, M. A.
van Waarde, A.
Dierckx, R. A. J. O.
de Vries, E. F. J.
author_facet Hartimath, S. V.
Khayum, M. A.
van Waarde, A.
Dierckx, R. A. J. O.
de Vries, E. F. J.
author_sort Hartimath, S. V.
collection PubMed
description PURPOSE: Chemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[(11)C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[(11)C]methyl-AMD3465 in rats bearing a C6 tumor and assessed whether the CXCR4 occupancy by the drug Plerixafor® can be measured with this PET tracer. PROCEDURE: A subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-[(11)C]methyl-AMD3465 PET scans with arterial blood sampling was performed in control rats and rats pretreated with Plerixafor® (30 mg/kg, s.c). The distribution volume (V (T)) of the tracer was estimated by compartment modeling with a two-tissue reversible compartment model (2TRCM) and by Logan graphical analysis. The non-displaceable binding potential (BP(ND)) was estimated with the 2TRCM. Next, CXCR4 receptor occupancy of different doses of the drug Plerixafor® (0.5–60 mg/kg) was investigated. RESULTS: The tumor could be clearly visualized by PET in control animals. Pretreatment with 30 mg/kg Plerixafor® significantly reduced tumor uptake (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). N-[(11)C]Methyl-AMD3465 was slowly metabolized in vivo, with 70 ± 7% of the tracer in plasma still being intact after 60 min. The tracer showed reversible in vivo binding to its receptor. Both 2TRCM modeling and Logan graphical analysis could be used to estimate V (T). Pre-treatment with 30 mg/kg Plerixafor® resulted in a significant reduction in V (T) (2TCRM 0.87 ± 0.10 vs. 0.23 ± 0.12, p < 0.05) and BP(ND) (1.85 ± 0.14 vs. 0.87 ± 0.12, p < 0.01). Receptor occupancy by Plerixafor® was dose-dependent with an in vivo ED(50) of 12.7 ± 4.0 mg/kg. Logan analysis gave comparable results. CONCLUSION: N-[(11)C]Methyl-AMD3465 PET can be used to visualize CXCR4 expression and to calculate receptor occupancy. V (T) determined by Logan graphical analysis is a suitable parameter to assess CXCR4 receptor occupancy. This approach can easily be translated to humans and used for early drug development and optimization of drug dosing schedules.
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spelling pubmed-54986392017-07-21 N-[(11)C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs Hartimath, S. V. Khayum, M. A. van Waarde, A. Dierckx, R. A. J. O. de Vries, E. F. J. Mol Imaging Biol Research Article PURPOSE: Chemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[(11)C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[(11)C]methyl-AMD3465 in rats bearing a C6 tumor and assessed whether the CXCR4 occupancy by the drug Plerixafor® can be measured with this PET tracer. PROCEDURE: A subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-[(11)C]methyl-AMD3465 PET scans with arterial blood sampling was performed in control rats and rats pretreated with Plerixafor® (30 mg/kg, s.c). The distribution volume (V (T)) of the tracer was estimated by compartment modeling with a two-tissue reversible compartment model (2TRCM) and by Logan graphical analysis. The non-displaceable binding potential (BP(ND)) was estimated with the 2TRCM. Next, CXCR4 receptor occupancy of different doses of the drug Plerixafor® (0.5–60 mg/kg) was investigated. RESULTS: The tumor could be clearly visualized by PET in control animals. Pretreatment with 30 mg/kg Plerixafor® significantly reduced tumor uptake (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). N-[(11)C]Methyl-AMD3465 was slowly metabolized in vivo, with 70 ± 7% of the tracer in plasma still being intact after 60 min. The tracer showed reversible in vivo binding to its receptor. Both 2TRCM modeling and Logan graphical analysis could be used to estimate V (T). Pre-treatment with 30 mg/kg Plerixafor® resulted in a significant reduction in V (T) (2TCRM 0.87 ± 0.10 vs. 0.23 ± 0.12, p < 0.05) and BP(ND) (1.85 ± 0.14 vs. 0.87 ± 0.12, p < 0.01). Receptor occupancy by Plerixafor® was dose-dependent with an in vivo ED(50) of 12.7 ± 4.0 mg/kg. Logan analysis gave comparable results. CONCLUSION: N-[(11)C]Methyl-AMD3465 PET can be used to visualize CXCR4 expression and to calculate receptor occupancy. V (T) determined by Logan graphical analysis is a suitable parameter to assess CXCR4 receptor occupancy. This approach can easily be translated to humans and used for early drug development and optimization of drug dosing schedules. Springer US 2016-11-28 2017 /pmc/articles/PMC5498639/ /pubmed/27896627 http://dx.doi.org/10.1007/s11307-016-1028-8 Text en © The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Research Article
Hartimath, S. V.
Khayum, M. A.
van Waarde, A.
Dierckx, R. A. J. O.
de Vries, E. F. J.
N-[(11)C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs
title N-[(11)C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs
title_full N-[(11)C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs
title_fullStr N-[(11)C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs
title_full_unstemmed N-[(11)C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs
title_short N-[(11)C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs
title_sort n-[(11)c]methyl-amd3465 pet as a tool for in vivo measurement of chemokine receptor 4 (cxcr4) occupancy by therapeutic drugs
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498639/
https://www.ncbi.nlm.nih.gov/pubmed/27896627
http://dx.doi.org/10.1007/s11307-016-1028-8
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