title: Synthesis and characterization of radioiodinated (S)-5-iodonicotine: a new ligand for potential imaging of brain nicotinic cholinergic receptors by single photon emission computed tomography.
abstract: (S)-5-Iodonicotine (4a), an (S)-nicotine analog iodinated at the 5-position of the pyridine ring, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain nicotine receptors by single photon emission computerized tomography (SPECT). [125I]-(S)-Iodonicotine ([125I]-4a) was synthesized by the iododestannylation reaction under no-carrier-added conditions and purified by high-performance liquid chromatography (HPLC). The binding affinity of 4a for brain nicotine receptors was measured in terms of displacement of [3H]cytisine from binding sites in rat cortical membranes. The binding data revealed that the affinity of 4a was the same as that of (S)-nicotine and 80-fold higher than that of the (R)-enantiomer (4b). Biodistribution studies in mice disclosed that the brain uptake of [125I]-4a was rapid and profound. Regional cerebral distribution studies in rats by autoradiography disclosed that the accumulation of [125I]-4a was dense in the thalamus, intermediate in the cortex and striatum, and less marked in the cerebellum. Furthermore, the administration of (S)-nicotine reduced the uptake of [125I]-4a in the thalamus and resulted in a nearly identical level of radioactivity in the cerebellum. [125I]-(R)-5-Iodonicotine ([125I]-4b) showed more rapid washout from the brain and a less extensive regional cerebral distribution than the (S)-enantiomer ([125I]-4a). Thus, 4a bound to brain nicotine receptor in vivo, and therefore iodine-123-labeled 4a may be a potential radioligand for use in vivo cerebral nicotinic receptor studies by SPECT.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Saji
authors.forename: A
authors.initials: A
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Magata
authors.forename: Y
authors.initials: Y
authors.lastname: Ohmomo
authors.forename: Y
authors.initials: Y
authors.lastname: Kiyono
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: Y
authors.initials: Y
authors.lastname: Iida
authors.forename: Y
authors.initials: Y
authors.lastname: Yonekura
authors.forename: J
authors.initials: J
authors.lastname: Konishi
authors.forename: A
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002851:Chromatography, High Pressure Liquid; D051379:Mice; D009538:Nicotine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000032:analysis*; D013237:Stereoisomerism; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C098439:5-iodonicotine; D011978:Receptors, Nicotinic; D009538:Nicotine