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.

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

Elena Martino;Stefano Sainas;Agnese C. Pippione;Donatella Boschi;Marco L. Lolli
2019

Abstract

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.
19th edition of the Merck Young Chemists' Symposium (MYCS-2019)
Rimini
25 - 27 Novembre, 2019.
Merck Young Chemist Symposium 2019 (MYCS-2019)
114
114
Elena Martino, Stefano Sainas, Agnese C. Pippione, Donatella Boschi, Yu- Shin Ding, Marco L. Lolli
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1852025
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