(S)[C-11]NICOTINE AND (R)-[C-11]NICOTINE AND THE METABOLITE (R/S)-[C-11]COTININE - PREPARATION, METABOLITE STUDIES AND INVIVO DISTRIBUTION IN THE HUMAN BRAIN USING PET

In order to investigate [C-11]nicotine binding and metabolism in the living human brain by PET, routine protocols were developed for the preparation and purification of (S)- and (R)-[C-11]nicotine and the metabolite (R/S)-[C-11]cotinine. (S)- and (R)-[C-11]nicotine were prepared by N-methylation with [C-11]methyl iodide of the appropriate secondary amine, which was liberated in situ by 2,2,6,6,-tetramethylpiperidine (TMP) from its corresponding biscamsylate-salt. (R/S)-[C-11]Cotinine was prepared by N-methylation of the amide precursor using tetrabutylammonium hydroxide as a phase transfer catalyst. Straight-phase semipreparative HPLC was in all purifications found to be superior to reversed-phase since the contamination by the norcompounds was eliminated. Reaction in acetonitrile for both (S)- and (R)-[C-11]nicotine (5 min, 130-degrees-C) and (R/S)-[C-11]cotinine (1 min, 80-degrees-C) with subsequent straight-phase HPLC purification resulted in 35-45% radiochemical yield (from EOB and decay-corrected) with a total synthesis time of 30-35 min, a specific radioactivity of 1000-1500 Ci/mmol (37-55 GBq/mumol, EOS) and a radiochemical purity >99%. The uptake and distribution of these tracers in the human brain was studied in healthy volunteers by PET. The metabolite (R/S)-[C-11]cotinine did not cross the blood brain barrier to any significant degree. The amount of the total radioactivity representing (S)-[C-11]nicotine measured in plasma by HPLC was 75% at 4 min and 25% at 50 min.