N-11CMethyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 CXCR4 Occupancy by Therapeutic DrugsReportar como inadecuado

N-11CMethyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 CXCR4 Occupancy by Therapeutic Drugs - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Molecular Imaging and Biology

, Volume 19, Issue 4, pp 570–577

First Online: 28 November 2016


PurposeChemokine receptor 4 CXCR4 is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-Cmethyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography PET. We investigated the pharmacokinetics of N-Cmethyl-AMD3465 in rats bearing a C6 tumor and assessed whether the CXCR4 occupancy by the drug Plerixafor® can be measured with this PET tracer.

ProcedureA subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-Cmethyl-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 VT 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 BPND was estimated with the 2TRCM. Next, CXCR4 receptor occupancy of different doses of the drug Plerixafor® 0.5–60 mg-kg was investigated.

ResultsThe 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-CMethyl-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 VT. Pre-treatment with 30 mg-kg Plerixafor® resulted in a significant reduction in VT 2TCRM 0.87 ± 0.10 vs. 0.23 ± 0.12, p < 0.05 and BPND 1.85 ± 0.14 vs. 0.87 ± 0.12, p < 0.01. Receptor occupancy by Plerixafor® was dose-dependent with an in vivo ED50 of 12.7 ± 4.0 mg-kg. Logan analysis gave comparable results.

ConclusionN-CMethyl-AMD3465 PET can be used to visualize CXCR4 expression and to calculate receptor occupancy. VT 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.

Key WordsPet Logan graphical analysis Compartment modeling Receptor occupancy CXCR4 receptors imaging  Download fulltext PDF

Autor: S. V. Hartimath - M. A. Khayum - A. van Waarde - R. A. J. O. Dierckx - E. F. J. de Vries

Fuente: https://link.springer.com/

Documentos relacionados