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Updated: Nov 22, 2025
Pre-clinical Orthotopic Murine Model of Human Prostate Cancer
Published on: August 29, 2016
Preclinical evaluation of [18F]cabozantinib as a PET imaging agent in a prostate cancer mouse model
Vegard Torp Lien1, Sofie Celen2, Syed Nuruddin3
1Department of Pharmacy, University of Oslo, Boks 1068, Blindern, 0316 Oslo, Norway; Norwegian Medical Cyclotron Center, Oslo, Norway.
Introduction:
Cabozantinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma, and is currently in clinical trials for the treatment of prostate cancer and others. It exerts its therapeutic effect mainly through inhibition of the tyrosine kinases MET (hepatocyte growth factor receptor) and VEGFR2 (vascular endothelial growth factor receptor 2), in addition to several other kinases involved in cancer. PET imaging with TKIs such as [18F]cabozantinib could potentially aid in cancer diagnosis and guide treatment. This study aims to evaluate the utility of [18F]cabozantinib as a PET imaging probe in PC3 tumor xenografted mice.
Methods:
[18F]cabozantinib was evaluated in non-tumor and tumor bearing (PC3 xenografted) male mice by ex vivo biodistribution studies and in vivo μPET imaging. Pretreatment studies were performed in the tumor bearing mice with the MET inhibitor PF04217903. Mouse plasma was analyzed with HPLC to quantify radiometabolites. To further evaluate the binding specificity of [18F]cabozantinib, in vitro autoradiography studies on heart and PC3 tumor sections were performed in the presence of authentic cabozantinib or specific MET and VEGFR2 inhibitors.
Results:
Tissue distribution studies in non-tumor bearing mice revealed slow blood clearance, absence of brain uptake and a high myocardial uptake. In the tumor bearing mice, tumor uptake was low (0.58 ± 0.20% ID/g at 30 min post tracer injection), which was confirmed by μPET imaging. No differences in tissue distribution and kinetics were observed in both biodistributions and μPET studies after pretreatment with the MET inhibitor PF04217903. At 30 min post tracer injection, 60 ± 3% of the recovered radioactivity in plasma in non-tumor bearing mice was present as intact tracer. [18F]cabozantinib binding in vitro to heart and tumor tissues was partly blocked in the presence of selective MET and VEGFR2 inhibitors (up to 40% block). The fraction of non-specific binding was relatively high for both tissues (66% for heart and 39% for tumor).
Conclusion:
[18F]cabozantinib exhibits non-favorable properties as a PET imaging probe, demonstrated by slow excretion kinetics along with low tumor uptake and high non-specific binding in tumor and heart tissue. The results reflect cabozantinibs multi-kinase activity, making PET imaging of tumor specific kinase expression with [18F]cabozantinib challenging.
Insights
[18F]cabozantinib, a tyrosine kinase inhibitor, shows poor performance as a PET imaging probe due to slow clearance, low tumor uptake, and high non-specific binding. Its multi-kinase activity makes it challenging for imaging specific kinase expression in tumors.
Area of Science:
- Nuclear medicine
- Radiochemistry
- Oncology
Background:
- Cabozantinib is a tyrosine kinase inhibitor (TKI) used to treat various cancers.
- PET imaging with radiolabeled TKIs like [18F]cabozantinib could aid cancer diagnosis and treatment guidance.
- Cabozantinib targets MET and VEGFR2 kinases, among others involved in cancer progression.
Purpose of the Study:
- To evaluate the utility of [18F]cabozantinib as a Positron Emission Tomography (PET) imaging probe.
- To assess the biodistribution and tumor uptake of [18F]cabozantinib in a prostate cancer xenograft mouse model.
- To investigate the specificity of [18F]cabozantinib binding in vitro and in vivo.
Main Methods:
- Ex vivo biodistribution studies and in vivo microPET imaging were performed in non-tumor and PC3 tumor-bearing mice.
- Pretreatment with a MET inhibitor (PF04217903) was conducted to assess target engagement.
- In vitro autoradiography on heart and tumor sections evaluated binding specificity in the presence of inhibitors.
Main Results:
- Slow blood clearance, minimal brain uptake, and high myocardial uptake were observed in non-tumor mice.
- Low tumor uptake (0.58 ± 0.20% ID/g at 30 min) was confirmed by microPET imaging in tumor-bearing mice.
- MET inhibitor pretreatment did not alter biodistribution or kinetics; significant non-specific binding was noted in heart (66%) and tumor (39%).
Conclusions:
- [18F]cabozantinib demonstrated unfavorable properties for PET imaging, including slow excretion and low tumor uptake.
- High non-specific binding in both tumor and heart tissues limits its utility as a specific imaging probe.
- The multi-kinase inhibitory profile of cabozantinib poses challenges for PET imaging of tumor-specific kinase expression.
