The human casein kinase 1 (CK1) family of protein kinases are serine/threonine-specific enzymes, consisting of at least 6 different isoforms (α, γ1, γ2, γ3, δ, and ε). Deregulation of CK1 activity is linked to several pathological disorders and diseases like cancer, neurodegenerative diseases, and inflammatory disorders. CK1 has become an interesting molecular target for the treatment and PET (positron emission tomography) imaging of CK1 associated diseases such as cancer cell proliferation. Recently difluoro-dioxolo-benzoimidazol-benzamides have been developed as potent and selective CK1δ and CK1ε inhibitors with nanomolar inhibitory activity. We are interested in the development of PET CK1 imaging agents. Here we report the synthesis of a carbon-11-labeled difluoro-dioxolo-benzoimidazol-benzamide [11C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate. The reference standard methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate and its corresponding desmethylated precursor 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoic acid were synthesized from commercially available starting materials 2,2-difluorobenzo[d][1,3]dioxol-5-amine and 3-(methoxycarbonyl)benzoic acid in 6 steps with 45%, and 7 steps with 41% overall chemical yield, respectively. The target tracer [11C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate was prepared from the acid precursor with [11C]CH3OTf under basic condition (2 N NaOH) through O-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 30-40% radiochemical yield based on [11C]CO2 and decay corrected to EOB. The radiosynthesis was performed in a home-built automated 11C-radiosynthesis module. The radiochemical purity was &gt;99%, and specific activity at EOB was 370-1110 GBq/μmol.

Synthesis of [11C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate as a new potential PET agent for imaging of casein kinase 1

254th National Meeting (2017)

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