PubMed2005
UNLABELLED: We have previously found that smokers have reduced brain monoamine oxidase (MAO) A and B using positron emission tomography (PET) and the irreversible mechanism-based radiotracers [(11)C]-labeled clorgyline (CLG) and deprenyl (DEP) and their deuterated analogs (D CLG, D DEP). More recently, we have estimated MAO A and B activity in other organs using the deuterium isotope effect to determine binding specificity for MAO and a three-compartment model to estimate k(3), the model term proportional to MAO A activity. Here, we have investigated the robustness of the model term k(3) for estimating lung MAO A and B in light of our unexpected finding that lung MAO activity (k(3)) was reduced for smokers relative to nonsmokers, although radiotracer uptake in the lungs was similar at peak and plateau for the two groups. METHODS: Time-activity data from lung and arterial plasma were used from seven nonsmokers and seven smokers scanned previously with CLG and D CLG, and five nonsmokers and nine smokers scanned previously with DEP and D DEP. The measured time-activity curves for lung and plasma and 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 the differences between smokers and nonsmokers, and the stability of the parameter (k(3)) 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 were significantly lower for smokers relative to nonsmokers for all four tracers. However, although the peak and plateau of the lung time-activity curves were similar for smokers and nonsmokers, the decline in radioactivity from peak to plateau was slower for smokers for all tracers. Using a three-compartment irreversible model, we estimated the ratio of MAO subtypes A and B in normal lung tissue to be on the order of 3 to 1 (MAO A to B) and that smokers have reduced MAO levels for both subtypes as measured by the model parameter, k(3). The values of k(3) are insensitive to model assumptions of variations in air and tissue fraction in the PET voxel. Most of the effects of changes in these fractions are absorbed into the parameter K(1), which governs the plasma-to-tissue transfer of tracer and is a function of blood flow. K(1) was found to be larger in smokers, although the values depend upon model assumptions of air and tissue fractions. k(3) was found to be significantly lower in smokers; for CLG, a 50% reduction in MAO A for both CLG and D CLG was observed. For DEP, k(3) was also significantly lower in smokers with a reduction of approximately 80% in lung MAO B, although there was a very large coefficient of variation in the smoker's k(3). We also found larger values of lambda (K(1)/k(2)) for smokers relative to nonsmokers for all tracers consistent with a longer lung retention of the nonenzyme-bound tracer, which explains the slower decline in uptake from peak radioactivity for smokers. CONCLUSIONS: The measured arterial input function values for smokers and nonsmokers are significantly different for these two tracer pairs for nonsmokers and smokers particularly for the first few minutes after radiotracer injection. Model estimates of k(3) that indicate that smokers have lower lung MAO A and B activity than nonsmokers are robust and insensitive to variations in model assumptions for relative fractions of lung tissue, blood and air in the PET voxel. Although we have only investigated the behavior of [(11)C]clorgyline and [(11)C]l-deprenyl and their deuterium-substituted analogs in this report, the extent to which reduced arterial input and longer lung retention also hold for other tracers for subjects who smoke merits investigation.