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

(S)-5-Iodonicotine (4a), an (S)-nicotine analog iodinated at the 5-pos ition of the pyridine ring, was synthesized and evaluated as a potenti al radiopharmaceutical for investigating brain nicotine receptors by s ingle photon emission computerized tomography (SPECT), [I-125]-(S)-5-I odonicotine ([I-125]-4a) was synthesized by the iododestannylation rea ction under no-carrier-added conditions and purified by high-performan ce liquid chromatography (HPLC). The binding affinity of 4a for brain nicotine receptors was measured in terms of displacement of [H-3]cytis ine from binding sites in rat cortical membranes. The binding data rev ealed 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 [I-125]-4a was rapi d and profound. Regional cerebral distribution studies in rats by auto radiography disclosed that the accumulation of [I-125]-4a was dense in the thalamus, intermediate in the cortex and striatum, and less marke d in the cerebellum. Furthermore, the administration of (S)-nicotine r educed the uptake of [I-125]-4a in the thalamus and resulted in a near ly identical level of radioactivity in the cerebellum, [I-125]-(R)-5-I odonicotine ([I-125]-4b) showed more rapid washout from the brain and a less extensive regional cerebral distribution than the (S)-enantiome r ([I-125]-4a). Thus, 4a bound to brain nicotine receptors in vivo, an d therefore iodine-123-labeled 4a may be a potential radioligand for u se in in vivo cerebral nicotinic receptor studies by SPECT.