Synthesis of [18F]Brequinar as PET Imaging probes for human dihydroorotate dehydrogenase

Human dihydroorotate dehydrogenase (hDHODH), a key enzyme involved in the pyrimidine biosynthesis, is a validate target for the treatment of autoimmune diseases and recently for acute myeloid leukemia (AML) [1]. In recent years, our group discovered a new class of hDHODH inhibitors based on the hydroxypyrazole scaffold [2] (1; Fig 1). For the purpose of in vivo imaging of hDHODH activity, we started from brequinar, one of the most potent hDHODH inhibitors so far discovered [3], to design a novel [18F]brequinar-based Positron Emission Tomography (PET) probes (2, 3). During the design of potential F-18 radiolabeling strategies, direct conversion of arylboronate esters, arylstannates and arylheteroaryliodonium salts to aryl fluorides has been investigated. These F-18 radiolabeled compounds will be further evaluated in animal models. These tools will allow the PET imaging of in vivo hDHODH activity, with important implications for clinical practice: assisting in early detection and monitoring disease, assessment of treatment efficacy, or development of new therapies. Based on the outcome of these studies, a similar approach will then be applied to our in-house designed hDHODH inhibitors.