Small-conductance Ca2+-activated K+ channels (SKCa) are widely expressed in different tissues such as the brain, peripheral nervous system, skeletal muscle, smooth muscle, heart and cancers, and regulate cognitive dysfunction, neuronal hyperexcitability, dopamine-related disorders, depression, hormone secretion from endocrine cells, and repolarization of cardiac action potentials. N-methyl-laudanosine (6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide, NML) is a reversible and selective SKCa channel blocker/inhibitor with high affinity. N-[11C]methyl-laudanosine (6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-[11C]methyl-2-methyl-1,2,3,4-tetrahydroisoquinolinium triflate, [11C]NML) was synthesized as a potential PET (positron emission tomography) SKCa  imaging agent. The precursor 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline was commercially available, and the methylation of the tertiary amine precursor with methyl iodide provided NML in 88% yield. The target quaternary ammonium tracer [11C]NML was prepared by the N-[11C]methylation of its corresponding precursor using [11C]CH3OTf and purified by a simplified solid-phase extraction (SPE) method using a cation-exchange CM Sep-Pak cartridge in 50-65% radiochemical yield based on [11C]CO2 and 20 min overall synthesis time from end of bombardment (EOB). The radiosynthesis was performed in a home-built automated multi-purpose 11C-radiosynthesis module. The specific activity, radiochemical purity and chemical purity of [11C]NML were determined by analytical HPLC as 6-20 Ci/�mol, >99% and >87%, respectively.

Fully automated SPE-based high-yield synthesis of N-[11C]methyl-laudanosine for imaging of small-conductance Ca2+-activated K+ channels

246th National Meeting (2013)

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