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

Abstract

ABT-418 ((S)-3-methyl-5-[l-methyl-2-pyrrolidinyl]isoxazole) and N-methylcytisine (N-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido-[ I,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-methylcytisine. ABT-418 and N-methylcytisine were labelled using ["Cjmethyl 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 ["Clnicotine, 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, "C-labelled N-methylcytisine does not appear to be a suitable ligand for mapping brain nAChR. E Dolle er a/.

In Vitro Evaluation of 11C‐Labeled (S)‐Nicotine, (S)‐3‐Methyl‐5‐(1‐Methyl‐2‐Pyrrolidinyl)isoxazole, and (R,S)‐1‐Methyl‐2‐(3‐Pyridyl)azetidine as Nicotinic Receptor Ligands for Positron Emission Tomography Studies

“…The very high affinity of ["CIMPA for nAChRs, the low nonspecific binding in the autoradiograms, and especially the slower dissociation kinetics of the ["C] MPA from the putative high-affinity nAChR binding site compared with (5)-["CI nicotine and ["C] ABT-41 8 focus interest on ["C]MPA as a candidate for in vivo studies. The novel radioligands ["C] ABT-418 and N-["C] methylcytisine have recently been reported by Valette et al (1997) and Dolle et al (1996) not to be suitable as radioligands in PET studies in monkeys. This finding is in agreement with in vivo observations for ["CIABT-418 from our laboratory (manuscript in preparation).…”

“…Furthermore, tests of the suitability of other potent~nAChR ligands for use in PET studies are still ongoing. Recently, (S)-3-methyl-5-( 1methyl-2-pyrrolidinyl)isoxazole (ABT-418) and Nmethylcytisine were labeled with ttC and applied in monkeys, but these results were less promising (Dolle et al, 1996;Valette et al, 1997).…”

(−)-Cytisine and Derivatives: Synthesis, Reactivity, and Applications

“…Dollé et al in 1996 described the synthesis and in vivo evaluation of N -[ 11 C]­methylcytisine. This radioligand was synthesized in 25–30 min (from the end of irradiation, HPLC purification included) by reaction of [ 11 C]­iodomethane with cytisine (−)- 1 .…”