Department of Pharmacy, University of Oslo, Boks 1068, Blindern, 0316 Oslo, Norway; Norwegian Medical Cyclotron Center, Oslo, Norway.
Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Nucl Med Biol. 2021 Feb;93:74-80. doi: 10.1016/j.nucmedbio.2020.12.002. Epub 2020 Dec 23.
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 [F]cabozantinib could potentially aid in cancer diagnosis and guide treatment. This study aims to evaluate the utility of [F]cabozantinib as a PET imaging probe in PC3 tumor xenografted mice.
[F]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 [F]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.
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. [F]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).
[F]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 [F]cabozantinib challenging.
卡博替尼是一种酪氨酸激酶抑制剂（TKI），已被批准用于治疗甲状腺髓样癌、肾细胞癌和肝细胞癌，目前正在临床试验中用于治疗前列腺癌和其他癌症。它主要通过抑制酪氨酸激酶 MET（肝细胞生长因子受体）和 VEGFR2（血管内皮生长因子受体 2）发挥治疗作用，此外还涉及其他几种参与癌症的激酶。使用 [F]卡博替尼等 TKI 进行 PET 成像可能有助于癌症诊断和指导治疗。本研究旨在评估 [F]卡博替尼作为 PC3 肿瘤异种移植小鼠 PET 成像探针的效用。
通过非肿瘤和肿瘤（PC3 异种移植）荷瘤雄性小鼠的体外生物分布研究和体内 μPET 成像评估 [F]卡博替尼。在肿瘤荷瘤小鼠中进行 MET 抑制剂 PF04217903 的预处理研究。使用 HPLC 分析小鼠血浆以定量放射性代谢产物。为了进一步评估 [F]卡博替尼的结合特异性，在存在真实卡博替尼或特异性 MET 和 VEGFR2 抑制剂的情况下，对心脏和 PC3 肿瘤切片进行体外放射自显影研究。
在非肿瘤荷瘤小鼠中的组织分布研究表明，血液清除缓慢，脑摄取不存在，心肌摄取高。在肿瘤荷瘤小鼠中，肿瘤摄取率低（示踪剂注射后 30 分钟时 0.58±0.20%ID/g），这通过 μPET 成像得到证实。在用 MET 抑制剂 PF04217903 预处理后，在生物分布和 μPET 研究中均未观察到组织分布和动力学的差异。在非肿瘤荷瘤小鼠中，示踪剂注射后 30 分钟，回收的放射性活度的 60±3%以完整示踪剂的形式存在。[F]卡博替尼与心脏和肿瘤组织的体外结合在存在选择性 MET 和 VEGFR2 抑制剂时部分被阻断（高达 40%的阻断）。两种组织的非特异性结合比例相对较高（心脏为 66%，肿瘤为 39%）。
[F]卡博替尼作为 PET 成像探针表现出不理想的特性，表现为排泄动力学缓慢，肿瘤摄取率低，肿瘤和心脏组织中的非特异性结合率高。这些结果反映了卡博替尼的多激酶活性，使得使用 [F]卡博替尼对肿瘤特异性激酶表达进行 PET 成像具有挑战性。
