Synthesis of a 11C-Isotopologue of the B-Raf-Selective Inhibitor Encorafenib Using In-Loop [11C]CO2 Fixation.

Mark H Dornan,Mehdi Boudjemeline,Roxana Mititelu,Daniil Petrenyov,Anthony P Belanger,José-Mathieu Simard,Jean N Dasilva

doi:10.1021/acsomega.0c02419

Abstract

The serine/threonine kinase B-Raf is an essential regulator of cellular growth, differentiation, and survival. B-Raf protein expression is elevated throughout melanoma progression, making it an attractive target for noninvasive imaging using positron–emission tomography. Encorafenib is a potent and highly selective inhibitor of B-Raf used in the clinical management of melanoma. In this study, the radiosynthesis of a 11C-isotopologue of encorafenib was developed using an in-loop [11C]CO2 fixation reaction. Optimization of reaction conditions reduced the formation of a radiolabeled side product and improved the isolated yields of [11C]encorafenib (14.5 ± 2.4% radiochemical yield). The process was fully automated using a commercial radiosynthesizer for the production of 6845 ± 888 MBq of [11C]encorafenib in high molar activity (177 ± 5 GBq μmol–1), in high radiochemical purity (99%), and in a formulation suitable for animal injection. An in vitro cellular binding experiment demonstrated saturable binding of the radiotracer to A375 melanoma cells.

Highlights

Melanoma is an aggressive form of skin cancer, which accounted for approximately 59,782 deaths and 351,880 new patients worldwide in 2015.1,2 localized melanoma is highly curable, patients diagnosed with metastatic disease face a 25% 5-year survival rate.[3]
We describe the development and optimization of the radiosynthesis of [11C]encorafenib, constructed using an in-loop [11C]CO2 fixation reaction
To label encorafenib with carbon-11, it was hypothesized that a [11C]CO2 fixation reaction developed by Wilson and co-workers could be used to radiolabel the carbonyl of the methylcarbamate fragment.[18]

Summary

INTRODUCTION

Melanoma is an aggressive form of skin cancer, which accounted for approximately 59,782 deaths and 351,880 new patients worldwide in 2015.1,2 localized melanoma is highly curable, patients diagnosed with metastatic disease face a 25% 5-year survival rate.[3]. The protein B-Raf (encoded by the gene BRAF) is an oncogenic serine/threonine kinase, which plays a pivotal role in the MAPK/ERK signal transduction pathway, a regulator of cell differentiation, proliferation, and survival.[4] Interestingly, studies have shown that B-Raf levels are significantly increased throughout the progression of melanoma in both wild-type and BRAF-mutated tumors.[5−8] Elevated B-Raf was observed in both primary and metastatic lesions and associated with aggressive tumor features and reduced survival This hints at a potential prognostic value that B-Raf protein expression may provide. Preliminary in vitro evaluation of the radiotracer was completed using A375 melanoma cells

RESULTS AND DISCUSSION

CONCLUSIONS

METHODS

■ ACKNOWLEDGMENTS

■ REFERENCES