Vegard Torp Lien1, Sofie Celen2, Syed Nuruddin3, Bala Attili2, Gilles Doumont4, Gaetan Van Simaeys5, Guy Bormans2, Jo Klaveness6, Dag Erlend Olberg7. 1. Department of Pharmacy, University of Oslo, Boks 1068, Blindern, 0316 Oslo, Norway; Norwegian Medical Cyclotron Center, Oslo, Norway. Electronic address: v.t.lien@farmasi.uio.no. 2. Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. 3. Norwegian Medical Cyclotron Center, Oslo, Norway. 4. Center for Microscopy and Molecular Imaging (CMMI), Université libre de Bruxelles (ULB), Charleroi, Belgium. 5. Center for Microscopy and Molecular Imaging (CMMI), Université libre de Bruxelles (ULB), Charleroi, Belgium; Department of Nuclear Medicine, Erasme University Hospital, Université libre de Bruxelles (ULB), Brussels, Belgium. 6. Department of Pharmacy, University of Oslo, Boks 1068, Blindern, 0316 Oslo, Norway. 7. Department of Pharmacy, University of Oslo, Boks 1068, Blindern, 0316 Oslo, Norway; Norwegian Medical Cyclotron Center, Oslo, Norway.
Abstract
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.
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 PC3tumor 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 PC3tumor 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.
Authors: Anita Thomas; Kimberly Sue Slade; Roman A Blaheta; Sascha D Markowitsch; Philipp Stenzel; Katrin E Tagscherer; Wilfried Roth; Mario Schindeldecker; Martin Michaelis; Florian Rothweiler; Jaroslav Cinatl; Robert Dotzauer; Olesya Vakhrusheva; Maarten Albersen; Axel Haferkamp; Eva Juengel; Jindrich Cinatl; Igor Tsaur Journal: Cancers (Basel) Date: 2022-03-25 Impact factor: 6.639
Authors: Julie Bolcaen; Shankari Nair; Cathryn H S Driver; Tebatso M G Boshomane; Thomas Ebenhan; Charlot Vandevoorde Journal: Pharmaceuticals (Basel) Date: 2021-06-29