We have previously shown that smokers have reduced human brain monoamine oxidase A and B (MAO A and B) using PET and the irreversible mechanism-based radiotracers [ 11 C]clorgyline and [ 11 C]deprenyl (CLG and DEP) and their deuterium-substituted derivatives (D CLG, D DEP) (Fowler er al., 1996). We also compared MAO in peripheral organs in non-smokers and smokers using the deuterium isotope effect to assess specificity for MAO. In applying a three-compartment model to time-activity data for the lung, we found that smokers had reduced k3, the model term proportional to MAO activity, even though the lung uptake at plateau was similar for the two groups. To investigate the factors contributing to a reduced value of k3 even when the plateau phase of the time-activity curves were similar, we re-examined the radiotracer kinetics and the robustness of the model term k3 for estimating lung MAO A and B. Methods: Time-activity data from lung and arterial plasma over a 60 min study time were used from 7 non-smokers and 7 smokers scanned with CLG and D CLG and 5 non-smokers and 9 smokers scanned previously with DEP and D DEP (Fowler et al., 2003). The integrals for the arterial plasma time-activity curves were compared at an early time point (2.5 min) and at the end of the study (55 min). A three-compartment irreversible model was used to estimate differences between smokers and nonsmokers for K1 (plasma to lung transfer term) and the stability of the model term k3 while varying model assumptions for the relative fractions of lung tissue, blood and air in the PET voxel. Results: The peak in the arterial plasma input function and the integral of the arterial plasma time-activity curve over the first 2.5 min after radiotracer injection was significantly lower for smokers for both CLG and D CLG and DEP and D DEP. Peak and plateau C-11 concentration in the lung was similar for the two groups. However, the decline from peak to plateau for the lungs (occurring โผ2-20 minutes post injection) was slower for smokers. K1 was larger in smokers, while k3 was found to be significantly lower in smokers (p<0.0005) indicating a 50% reduction in MAO A for both CLG and D CLG. For DEP, k3 was also significantly lower in smokers (p<0.0005) giving a reduction of โผ80% in lung MAO B although there was a very large coefficient of variation in the smoker's k3. Values of ฮป (K1/k2) were also larger for smokers consistent with a longer lung retention of the non-MAO-bound tracer which is consistent with the slower decline in uptake from peak to plateau for smokers for the lungs. The values of k3 are insensitive to model assumptions of variations in air and tissue fraction in the PET voxel. Conclusions: Model estimates of k3, which indicate that smokers have lower lung MAO A and B activity than nonsmokers, are robust and are insensitive to variations in model assumptions for relative fractions of lung tissue, blood and air in the PET voxel. The values of k3 are largely governed by the slower clearance of non-MAO-bound radioactivity from the lung. This may reflect tobacco-smoke-induced inflammatory processes and cell injury. This study also revealed that the concentration of the MAO A and B radiotracers in the arterial plasma at short times after radiotracer injection is significantly lower for smokers which may be due to retention by the smoker's lungs. If this is generally true for other substances which are administered intravenously, then this needs to be considered as a variable which may contribute to different short term behavioral and therapeutic responses to intravenously administered compounds for non-smokers vs smokers. Supported by DOE-OBER and NIH.