Alzheimer’s disease (AD) is a complicated neurodegenerative disorder, and none effective strategy is approved for preventing, curing and slowing the progress of AD. The available medications such as AChEIs and a NMDA receptor antagonist can only be used to treat the cognitive problems of AD. Serotonin 6 receptor (5-HT6R) has become a promising alternative target for symptomatic treatment of AD, and 5-HT6R antagonists have been hypothesized to improve cognition, learning, and memory. Recently a new series of 5-HT6R antagonists has been developed by Suven for potential treatment of AD, and the representative compounds, 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole (1a), 5-methoxy-3-((4-methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (1b), 1-((4-isopropylphenyl)sulfonyl)-5-methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (1c) and 1-((4-fluorophenyl)sulfonyl)-5-methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (1d), exhibited high binding affinity to human 5-HT6R with Ki value 2.0, 4.3, 1.6 and 5.0 nM, respectively, and high selectivity over 100 target sites. We are interested in the development of PET AD imaging agents. Here we present a fully automated radiosynthesis of carbon-11-labeled 5-HT6R antagonists as new candidate PET radioligands for imaging of AD. 1-[(2-Bromophenyl)sulfonyl]-5-[11C]methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole (O-[11C]1a) and 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-[11C]methyl-1-piperazinyl)methyl]-1H-indole (N-[11C]1a), 5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (O-[11C]1b) and 5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (N-[11C]1b), 1-((4-isopropylphenyl)sulfonyl)-5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[11C]1c) and 1-((4-isopropylphenyl)sulfonyl)-5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1H-indole (N-[11C]1c), 1-((4-fluorophenyl)sulfonyl)-5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[11C]1d) and 1-((4-fluorophenyl)sulfonyl)-5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1H-indole (N-[11C]1d), were prepared from their O- or N-desmethylated precursors with [11C]CH3OTf through O- or N-[11C]methylation and isolated by HPLC-SPE method in 40-50% decay corrected radiochemical yield. The radiochemical purity was &gt;99%, and the molar activity (MA) at EOB was 370-740 GBq/μmol with a total synthesis time of ~40-minutes from EOB.

Fully automated radiosynthesis of carbon-11-labeled 5-HT6R antagonists as new candidate PET radioligands for imaging of Alzheimer’s disease

256th National Meeting (2018)

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