PET studies of the uptake of (S)- and (R)-[11C]nicotine in the human brain: difficulties in visualizing specific receptor binding in vivo

Abstract

(S)- and (R)-[11C]nicotine were synthesized by methylation of (S)- and (R)-nornicotine using [11C]methyl iodide. Following their intravenous injection in tracer doses to smoking and nonsmoking healthy males the radioactivity in arterial blood showed a sharp peak at about 1 min followed by a plateau level for the remaining 50 min of recording. Uptake in the brain, as measured by positron emission tomography (PET), was rapid with a peak at 5 min followed by a steady decline towards the end of the measurement. The regional distribution of radioactivity followed essentially the distribution of gray matter with high uptake in the cortex, the thalamus and the basal ganglia and low uptake in the pons, cerebellum and white matter. Levels of the labelled natural enantiomer, (S)-[11C]nicotine, were higher than those of the synthetic enantiomer, (R)-[11C]nicotine, particularly in the smokers. The time-activity curves of (S)-[11C]nicotine uptake were not changed by co-administration of 1.0 mg of unlabelled nicotine with the labelled nicotine. Similarly administration of unlabelled nicotine at the peak of radioactivity, 6 min following (S)-[11C]nicotine, had no effect on the time-activity curves. Thus essential criteria for visualizing receptor binding with the PET technique could not be fulfilled. Calculation of kinetic constants using a two-compartment model gave values indicating that the brain uptake of [11C]nicotine is mainly determined by the cerebral blood flow, extraction of the tracer over the blood-brain barrier and unspecific binding. Thus 11C-labelled nicotine does not seem to be a suitable tracer for PET studies of nicotinic cholinergic receptors in the human brain.

Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11 C-nicotine

“…In this study, the maximal boost in arterial concentration of nicotine was determined to be 27 ng/mL (167 nM). Assuming the V T value for the entire brain as 2.6 [3.0 and 2.2 for gray and white matter, respectively (23)], the boost in total brain nicotine concentration was calculated to be 434 nM. Overall, the good agreement between this value and that obtained in the present study (357 nM) verifies the validity of our approach and our assumptions.…”

5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

“…Radioligands developed for noninvasive in vivo imaging of ␣-bungarotoxin-insensitive nAChRs have exhibited shortcomings, such as poor subtype selectivity and high levels of nonspecific binding (Nybä ck et al, 1994 (Flores et al, 1996;Xiao et al, 1998). In contrast to ␣4␤2 nAChRs, nAChRs containing ␣3 and ␤4 subunits, possibly in combination with ␣5 subunits, are distributed mostly in the peripheral nervous system and adrenal glands (Holladay et al, 1997).…”

CYP2A6 and CYP2B6 are involved in nornicotine formation from nicotine in humans: Interindividual differences in these contributions

“…Therefore, the metabolism of nicotine to nornicotine would be a relatively minor pathway in the systemic clearance of nicotine. However, experimental animal studies revealed that nornicotine is present in brain at significant levels (approximately 20% of the total amount of nicotine and its metabolites) (Nordberg et al, 1989;Plowchalk et al, 1992;Nyback et al, 1994;Crooks et al, 1997). The nornicotine concentration in brain was nearly equal to that of nicotine (Crooks et al, 1997).…”