Synthesis and 11C-labelling of two selective high affinity nicotinic cholinergic agonists for evaluation as radioligands for PET studies

ABT-418 ((S)-3-methyl-5- [1-methyl-2-pyrrolidinyl]isoxazole) and N-methylcytisine (N-methyl-1,2,3,4,5,6-hexahydro-1,5-methano -8H-pyrido-[1,2-a] [1,5]diazocin-8-one) are two high affinity nicotinic cholinergic agonists. ABT-418 was synthesized in 7 steps from commercially available (S)-Boc-proline in 35% overall yield. Methylation of commercial cytisine cleanly gave N-methyl-cytisine. ABT-418 and N-methylcytisine were labelled using [11C]methyl iodide by methylation of the corresponding nor-precursors for their in vivo evaluation as positron emission tomography (PET) probes of the nicotinic cholinergic receptors in baboon brain. As for [11C]nicotine, specific binding in vivo could not be demonstrated for ABT-418. Therefore, further experiments are needed to determine the full PET pharmacological profile and the subsequent potential clinical applications of ABT-418 as a tracer for PET experiments. For labelled N-methyl-cytisine, radioactivity in the cerebral cortex and in the blood were similar. Thus, 11C-labelled N-methylcytisine does not appear to be a suitable ligand for mapping brain nAChR. (author)