Abstract
Trametinib (MEKINIST™) is an extremely potent allosteric inhibitor of MEK1/2 that has been approved for treatment of metastatic melanoma and anaplastic thyroid cancer in patients with confirmed BRAFV600E/K mutations. Though highly efficacious, adverse side effects including skin, gastrointestinal and hepatic toxicity, are dose limiting and can lead to treatment termination. Development of a non-invasive tool to visualize and quantify the delivery and distribution of trametinib (either as single agent or in combination with other therapeutics) to tumors and organs would be very helpful in assessing therapeutic index, personalizing individual dose and potentially predict resistance to therapy. To address these issues, we have developed a radiolabeled trametinib and evaluated the in vitro and in vivo properties. 123I-, 124I- and 131I-trametinib, pure tracer analogs to trametinib, were synthesized in >95% purity with average yield of 69.7% and >100GBq/µmol specific activity. Overall, 124I-trametinib uptake in a panel of cancer cell lines can be blocked with cold trametinib confirming specificity of the radiotracer in vitro and in vivo. 124I-Trametinib was taken up at higher rates in KRAS and BRAF mutant cell lines compared to wild type KRAS cancer cell lines. In vivo, biodistribution revealed high uptake in the liver 2 hours post injection followed by clearance through the gastrointestinal tract over 4 days. Importantly, higher than expected uptake was observed in the lung and heart for up to 24 hours. Peak uptake in the skin and gastrointestinal tract was observed between 6 and 24 hours while in B16F10 melanoma bearing mice peak tumor concentrations were achieved between 24 to 48 hours. Tumor uptake relative to muscle and skin was relatively low, peaking at 3.4- to 8.1-fold by 72 hours, respectively. Biodistribution of 124I-trametinib was significantly reduced in mice on trametinib therapy providing a quantitative method to observe MEK inhibition in vivo. 124I-trametinib serves as a tool to personalize in vivo the dose instead of using the current single fixed dose scheme and when combined with radiomic data monitor emergence of therapy resistance. In addition, the production of iodinated trametinib affords researchers the ability to measure drug distribution for improved drug delivery studies.
- Animal Imaging
- Molecular Imaging
- Oncology: Melanoma
- Radiochemistry
- MEK
- melanoma
- small molecule inhibitor
- trametinib
- Copyright © 2020 by the Society of Nuclear Medicine and Molecular Imaging, Inc.