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The article discusses the radiosynthesis of [18F]Brequinar for in vivo PET imaging of hDHODH enzyme, which could be used in studies of acute myeloid leukemia and cancers. The development of in vivo imaging probes is crucial for demonstrating target engagement to facilitate the development of therapeutic strategies. [18F]Brequinar is a potent hDHODH inhibitor, and the study presents strategies for its synthesis, radiolabeling, and preliminary PET imaging study of DHODH in vivo. This work could aid in drug development, diagnosis, and monitoring of therapeutic efficacy in AML and cancers.
Dihydroorotate dehydrogenase (DHODH), an enzyme that plays a critical role in the de-novo pyrimidine biosynthesis, has been recognized as a promising target for the treatment of diseases that involve cellular proliferation, such as autoimmune diseases and cancers. Pharmacological inhibition of human DHODH (hDHODH) that offers a potential therapeutic strategy for the treatment in adult subjects with acute myeloid leukemia (AML) has recently been supported by Phase I/II clinical trials for the treatment of patients with relapsed/refractory AML. To facilitate the development of optimized hDHODH inhibitors, the presence of an in vivo imaging probe that is able to demonstrate in vivo target engagement is critical and desirable. Brequinar is one of the most potent hDHODH inhibitors so far discovered. In this work, we use copper-mediated radiofluorination (CMRF) strategy and compare the chemical design and radiosynthesis starting from either pinacole boronate p-nitrobenzyl ester (4) or tributylstannate (tin) p-nitrobenzyl ester (5), chosen for their suitability as a precursor to [18F]brequinar. We report here the design, synthesis, radiolabeling and characterization of [18F]brequinar, and a preliminary PET imaging study of DHODH in vivo. This study provides the strategies to create [18F]brequinar, the first hDHODH inhibitor PET radiotracer, which will facilitate its use as a tool (theranostics) for hDHODH drug development and for diagnosis and monitoring therapeutic efficacy in AML and cancers.
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