The Raf family consists of serine/threonine kinases A-Raf, B-Raf and C-Raf (Raf-1). The V600E mutation of B-Raf kinase results in constitutive activation of the Ras/Raf/MEK/ERK (MARK) signaling pathway and is present in approximately 7% of all cancers. B-RafV600E has become an attractive target for cancer therapy, and a novel series of pyrazolopyridine inhibitors of B-RafV600E has been recently developed by Wenglowsky et al. B-RafV600E is an attractive target for molecular imaging of cancer as well. Here we report the first design and synthesis of 2,6-difluoro-N-(3-[11C]methoxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide as a new potential imaging agent for biomedical imaging technique positron emission tomography (PET) to image B-RafV600E in cancers. The authentic standard 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide (IC50 4.8 nM for B-RafV600E) was synthesized from 2,6-difluorobenzoic acid and 3-amino-5-hydroxypyrazole by the published procedures in 9 steps with 1% overall chemical yield. Direct desmethylation of the reference standard with chlorotrimethylsilane (TMSCl)/NaI gave the precursor 2,6-difluoro-N-(3-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide for radiolabeling in 70% yield. The target tracer was prepared from the precursor with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC in 40-50% decay corrected radiochemical yields from [11C]CO2 at EOB with 370-740 GBq/�mol specific activity at EOB.

Synthesis of 2,6-difluoro-N-(3-[11C]methoxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide as a new potential PET agent for imaging of B-RafV600E in cancers

245th National Meeting (2013)

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