Quantification of Smoking-Induced Occupancy of β2-Nicotinic Acetylcholine Receptors: Estimation of Nondisplaceable Binding

5-I-123-iodo-85380 (I-123-5-IA) is used to quantitate high-affinity nicotinic acetylcholine receptors (beta(2)-nAChRs) on human SPECT scans. The primary outcome measure is V-T/f(P), the ratio at equilibrium between total tissue concentration (free, nonspecifically bound, and specifically bound) and the free plasma concentration. Nondisplaceable uptake (free plus nonspecific) of I-123-5-IA has not been measured in human subjects. Nicotine has high affinity for beta(star)(2)-nAChRs (nAChRs containing the beta 2(star) subunit, for which (star) represents other subunits that may also be part of the receptor) and displaces specifically bound I-123-5-IA. In this study, we measured nicotine occupancy and nondisplaceable binding in healthy smokers after they had smoked to satiety. Methods: Eleven nicotine-dependent smokers (mean age +/- SD, 35.6 +/- 14.4 y) completed the study. One subject was excluded from subsequent analyses because of abnormal blood nicotine levels. Subjects abstained from tobacco smoke for 5.3 +/- 0.9 d and participated in a 15- to 17-h SPECT scanning day. I-123-5-IA was administered by bolus plus constant infusion, with a total injected dose of 361 +/- 20 MBq. At approximately 6 h after the start of the infusion, three 30-min SPECT scans and a 15-min transmission-emission scan were acquired to obtain baseline beta 2(star)-nAChR availability. Subjects then smoked to satiety (2.4 +/- 0.7 cigarettes), and arterial (first 40 min) and venous (until study completion) plasma nicotine and cotinine levels were collected. About 1 h after subjects had smoked to satiety, up to six 30-min SPECT scans were acquired. V-T/f(P) data, computed from the tissue and plasma radioactivity measurements from the presmoking baseline and postsmoking scans, were analyzed using the Lassen plot method. Results: Receptor occupancy after subjects had smoked to satiety was 67% +/- 9% (range, 55% 280%). Nondisplaceable uptake was estimated as 19.4 +/- 5.8 mL.cm(-3) (range, 15-28 mL.cm(-3)). Thus, in the thalamus, where mean V-T/f(P) is 93 mL.cm(-3), nondisplaceable binding represents approximately 20% of the total binding. Conclusion: These results are in agreement with previous findings and suggest that when satiating doses of nicotine are administered to smokers, imaging of receptor availability can yield valuable data, such as quantifiable measures of nondisplaceable binding.