Synthesis of [18F]norchlorofluoroepibatidine and its N-methyl derivative: new PET ligands for mapping nicotinic acetylcholine receptors

Fluorine-18 labeled norchlorofluoroepibatidine (NFEP), a high-affinity nicotinic acetylcholine receptor ligand, was prepared by a one-pot, two-step synthesis: nucleophilic heteroaromatic substitution of a tert-Boc protected precursor (7-tert-butyloxycarbonyl-exo-2-(2′-N,N,N-trimethylammonium-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane iodide) using no-carrier-added [18F]fluoride followed by deprotection with trifluoroacetic acid. Subsequent reductive N-methylation with formaldehyde and sodium cyanoborohydride afforded fluorine-18 labeled N-methyl-norchlorofluoroepibatidine (N-methyl-NFEP). The unusually high radiochemical yield for the first step (70%) and the quantitative conversions in the deprotection and N-methylation steps afforded overall radiochemical yields of 55–65% (decay corrected based on starting [18F]fluoride) for [18F]NFEP (synthesis time 65 min) and 45–55% for [18F]N-methyl-NFEP (synthesis time 75 min), with a specific activity of 2–9 Ci/μmole (EOB).