The epidermal growth factor receptor (EGFR) family of tyrosine kinases, also known as ErbB or HER receptors, comprises four related receptor kinases: EGFR (ErbB1, HER1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Deregulation of EGFR signaling is associated with the development of neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease, as well as various solid tumor. AZD8931 is an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors recently discovered by AstraZeneca, and the IC50 of AZD8931 is 4, 3, ad 4 nM for EGFR, HER2, and HER3, respectively. EGFR has become a promising target for molecular imaging of EGFR-related diseases and image-guided therapy using the biomedical imaging technique positron emission tomography (PET). Here we present a fully automated radiosynthesis in a home-built automated 11C-radiosynthesis module of [11C]AZD8931 as a candidate PET tracer for imaging of EGFR, HER2 and HER3 signaling. The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2-5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2-4% overall chemical yield. The target tracer [11C]AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-[11C]methylacetamide} ([11C]11a) was prepared from N-desmethyl-AZD8931 (11b) with [11C]CH3OTf under basic condition (NaH) through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB) with 370-1110 GBq/μmol specific activity at EOB.

Fully automated radiosynthesis of [11C]AZD8931 as a new PET agent for imaging of EGFR, HER2 and HER3 signaling

249th National Meeting (2015)

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