N-[11C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic
S V Hartimath1, M A Khayum1, A van Waarde1
1Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 31.001, 9713 GZ, Groningen, The Netherlands.
Purpose:
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.
Procedure:
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 (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 (BPND) 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-[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 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 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.
Conclusion:
N-[11C]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.
Insights
N-[11C]methyl-AMD3465 positron emission tomography (PET) effectively visualizes chemokine receptor 4 (CXCR4) expression and measures drug occupancy. This tracer enables dose-dependent assessment of Plerixafor® efficacy in preclinical models.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Pharmacology
Background:
- Chemokine receptor 4 (CXCR4) is frequently overexpressed in various cancers, presenting a significant therapeutic target.
- N-[11C]methyl-AMD3465 is a novel positron emission tomography (PET) tracer developed for imaging CXCR4 expression.
Purpose of the Study:
- To investigate the pharmacokinetics of N-[11C]methyl-AMD3465 in a rat tumor model.
- To assess the capability of this PET tracer to measure CXCR4 receptor occupancy by the drug Plerixafor®.
Main Methods:
- Dynamic PET scans with arterial blood sampling were conducted in Wistar rats bearing C6 tumors.
- Tracer distribution volume (VT) and binding potential (BPND) were estimated using compartment modeling (2TRCM) and Logan graphical analysis.
- CXCR4 receptor occupancy by varying doses of Plerixafor® was evaluated.
Main Results:
- N-[11C]methyl-AMD3465 clearly visualized tumors in control rats, with significant reduction in uptake upon Plerixafor® pretreatment.
- The tracer demonstrated slow metabolism and reversible binding in vivo.
- Significant reductions in VT and BPND were observed with Plerixafor® treatment, indicating dose-dependent receptor occupancy (ED50 = 12.7 ± 4.0 mg/kg).
Conclusions:
- N-[11C]methyl-AMD3465 PET is a viable tool for visualizing CXCR4 expression and quantifying receptor occupancy.
- Logan graphical analysis provides a suitable parameter (VT) for assessing CXCR4 receptor occupancy.
- This PET imaging approach is readily translatable to human studies for drug development and dose optimization.
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