Proto-oncogene serine/threonine-protein kinase (PIM1) is an emerging target for cancer therapy, and PIM1 inhibitors have been developed as anticancer drugs. (Z)-2-((1H-indazol-3-yl)methylene)-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one is a novel potent and selective PIM1 inhibitor with PIM1 IC50 3 nM. Here we report the synthesis of (Z)-2-((1H-indazol-3-yl)methylene)-6-[11C]methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one as a new potential PET agent for imaging of PIM1 in cancer. The reference standard, intermediate (Z)-tert-butyl 4-((2-((1H-indazol-3-yl)methylene)-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate and its Boc-protected precursor (Z)-tert-butyl 4-((2-((1H-indazol-3-yl)methylene)-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate for radiolabeling were synthesized from 6-hydroxybenzofuran-3(2H)-one and tert-butyl piperazine-1-carboxylate in 4, 3 and 2 steps with 29%, 35% and 44% overall chemical yield, respectively. The precursor was labeled with [11C]CH3OTf under basic conditions (2 N NaOH) through O-[11C]methylation to provide a radiolabeled intermediate (Z)-tert-butyl 4-((2-((1H-indazol-3-yl)methylene)-6-[11C]methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate, which was then quickly de-protected under acidic conditions (1 N HCl) to give the target tracer in 20-30% decay corrected radiochemical yield and 370-740 GBq/�mol specific activity at end of bombardment (EOB). The two-step radiolabeling reaction was performed in a home-built automated 11C-radiosynthesis module, and the target tracer was purified by HPLC method.

Synthesis of a carbon-11-labeled PIM1 inhibitor as a new potential PET agent for imaging of PIM1 in cancer

246th National Meeting (2013)

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