фторированные пиримиды 5-карбоксамиды в качестве потенциальных инструментов для разработки MERTK были нацелены на развитие фтора-18-PET-радиолиганда.
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Mudududdla Ramesh, Wong Siu Wai, Nguyen Nghi, Xue Lian, Stashko Michael A, Wang Xiaodong, Vivash Lucy, Binder Michele D, Ackermann Uwe, Bozikis Ylva E, Kilpatrick Trevor J, Baell Jonathan B
Аннотация
Оригинал публикации
Fluorinated pyrimidine 5-carboxamides as potential tools for MERTK targeted fluorine-18-PET-radioligand development.
MER tyrosine kinase (MERTK) is highly expressed on the protective and reparative phenotype of microglia, which is in response to neuroregeneration following the neuronal damage induced by multiple sclerosis (MS). A specific imaging tool, which can differentiate anti-inflammatory and immunosuppressive responses of microglia, could be highly beneficial for the early detection and clinical management of MS. To identify potential 18F-radiotracers to image anti-inflammatory responses of microglia, herein a series of fluorinated pyrimidine-5-carboxamide derivatives were prepared from a database of MERTK ligands. Several potent MERTK ligands were discovered with promising selectivity profiles over other off-targets (AXL, TYRO3 and FLT3). A cell-based assay was employed to assess cellular inhibitory MERTK potency, which may be regarded as being particularly relevant to an in vivo imaging situation. This study reports the discovery of several new, potent, and selective fluorinated compounds against MERTK, paving the way for PET tracer development to image protective microglial phenotype in MS patients.