Modeling lung MAO A and B in smokers and nonsmokers with [11C]clorgyline and [11C]deprenyl

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Modeling lung MAO A and B in smokers and
nonsmokers with 11Cclorgyline and 11Cdeprenyl
Jean Logan, Joanna Fowler, Gene-Jack Wang, Nora
Volkow, Frank Telang, David Alexoff
Brookhaven National Laboratory
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Monoamine Oxidase

• Oxidizes neurotransmitters and dietary amines and
  produces hydrogen peroxide
• Two subtypes (MAO A and MAO B) which are
  different gene productsMAO A oxidizes NE, 5HT,
  DAMAO B oxidizes PEA, DA
• A key regulatory enzyme in brain and in
  peripheral organs

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MAO Tracers for PET
11C Deprenyl (DEP) tracer for MAO B 11C
Clorgyline (CLG) tracer for MAO A
The deuterium isotope effect is used to assess
binding specificity
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model of lung uptake
k3 (MAO) a k'E
K1 plasma to tissue (Blood Flow)
tissue F (free) T (bound to MAO)
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MAO in Smokers vs Nonsmokers
Smokers have reduced MAO A and B in brain
(k3) reduced MAO B but not A in heart, kidney
reduced MAO A and MAO B in lungs but lung
uptake is similar for both smokers and nonsmokers
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Purpose To investigate factors contributing to
tracer uptake in lung tissue of smokers and
nonsmokers in order to understand why uptake is
similar for both groups but MAO reduced.
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Methods
PET Studies (lung) with tracers CLG,
DEP D-CLG
D-DEP
CLG D-CLG 7 SMK 7 NSMK
DEP D-DEP 9 SMK 5 NSMK
Arterial blood samples corrected for metabolites
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Lung uptake averaged over subjects
Dose/cc
Dose/cc
Time (min)
Dose/cc
Dose/cc
Time (min)
Time (min)
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Observations

• Peak uptake similar in both smokers and
  nonsmokers for all tracers
• Similar plateau for both S and NS
• Slower decline from peak to plateau in smokers
  lungs for both CLG and DEP
• The isotope effect can be seen in the difference
  in the uptake plateau of CLG and D CLG times gt 30
  min (need to model)

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Plasma input functions averaged over subjects
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Plasma integral at 2.5 min is 30 lower in smokers
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K1(Smokers) gt K1 (Nonsmokers)
11CLdeprenyl (MAO B)
11Cclorgyline (MAO A)
Voxel fractions Air 0.7 Tiss 0.2 Blood 0.1
K1 depends on voxel fractions
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Comparison of l K1/k2 (partition coefficient)
for non-smokers and smokers
?
11Cclorgyline MAO A
11CLdeprenyl (MAO B)
? S gt NS gt tracer is retained in tissue of
smokers longer than nonsmokers
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Comparison of k3
D DEP
DEP
CLG
D CLG

• Smoking effect S lt NS (all tracers)
• Isotope effect CLG (NS, S) DEP (NS)
• k3 (DEP) gt k3(CLG) (NS) (0.14 .08 min-1)

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Lung uptake and model fit for a smoker and
nonsmoker D CLG.
Components of model fit
K1 2.34, 5.08 ml/g/min, ? 8.27, 5.47 ml/g and k3
0.016, 0.038 min-1 (Smoker, Nonsmoker)
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Other Ligands Plasma integral at 2.5 min
11Ccocaine
p.012
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Summary

1. Smokers have a significantly larger K1 due to a
   lower arterial plasma input in the initial few
   minutes after tracer injection.
2. k3(S) lt k3 (NS) k3 not sensitive to
   variations in voxel fractions
3. ?(S) gt ?(NS) Longer retention in lung of
   non-enzyme bound tracer. Smokers have less MAO
   bound tracer but more nonenzyme bound tracer due
   to the longer retention

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Relationship to other studies
(1) Rose JE et al, Drug and Alcohol Dependence
56 99-107, 1999
After iv injection of nicotine to smokers, the
delivery of nicotine into arterial blood is
substantially slower than would be predicted if
nicotine were absorbed as rapidly as has
generally been assumed. A plausible explanation
is that lung uptake of nicotine considerable
slows the entry of nicotine into systemic
circulation. These results have significant
implications for theories of addiction to
nicotine as well as other drugs such as cocaine
that may be subject to binding by lung tissue.
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(2) Kagaya A et al , Pulmonary kinetics of
13N-ammonia in smoking subjects--a quantitative
study using dynamic PETKaku Igaku, 29
1099-106, 1992. The activity(TAC) curve
demonstrated a biexponential clearance from the
lung with fast and slow components A significant
increase of retention fraction and prolongation
of t1/2 of slow component were observed in
smokers compared to non-smokers and exsmokers.
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Brookhaven Center for Translational Neuroimaging
David Alexoff, Karen Apelskog, Nicole Barbarich,
Helene Benveniste,Anat Biegon, Elisabeth
Caparelli, Pauline Carter, Stephen Dewey, Yu-Shin
Ding, Congwu Du, Richard Ferrieri, Bernd
Foerster, Joanna Fowler, John Gatley, Andrew
Gifford, Rita Goldstein, Bud Jayne, Kun-eek Kil,
Sunny Kim, Payton King, Nellie Klein, Aarti
Kriplani, Kuo-Shyan Lin, Jean Logan, Jeming Ma,
Doug Marsteller, Martine Mirrione, Lisa Muench,
William Rooney, Colleen Shea, Wynne Schiffer,
David Schlyer, Mike Schueller, Sepi Shokouhi,
Dardo Tomasi, Frank Telang, Paul Vaska, Nora
Volkow, Gene-Jack Wang, Donald Warner, Chris
Wong, HaiTau Wu, Youwen Xu, Wei Zhu
Funded by DOE-OBER, NIH and ONDCP
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k3 (DEP) 1.8 CLG From
post-mortem studies the concentration of MAO A is
higher in human lung. The ligand-enzyme
association constant is greater for DEP than CLG
DEP MAO B IC50 of 6.8 nM CLG MAO A IC50
of 39 nM k3(CLG)/ k3(DEP)EMAOAkon(CLG)/
EMAOBkon(DEP) EMAOA/ EMAOB (0.078 x 39)/
(0.143 x 6.8) 31
Mukherjee and Yang Saura et al 2 fold A
to B