Chemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[11C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[11C]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.
A subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-[11C]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 (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.
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-[11C]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 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.
N-[11C]Methyl-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.
Fran B (2004) The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol 14:171–179 CrossRef
Rempel SA, Dudas S, Ge S, Gutierrez JA (2000) Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6:102–111 PubMed
Domanska UM, Kruizinga RC, den Dunnen WFA et al (2011) The chemokine network, a newly discovered target in high grade gliomas. Crit Rev Oncol 79:154–163 CrossRef
Hattermann K, Mentlein R, Held-Feindt J (2012) CXCL12 mediates apoptosis resistance in rat C6 glioma cells. Oncol Rep 27:1348–1352 PubMed
- N-[11C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs
S. V. Hartimath
M. A. Khayum
A. van Waarde
R. A. J. O. Dierckx
E. F. J. de Vries
- Springer US
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