J Logan,Yu-Shin Ding, Kuo-Shyan Lin, Deborah Pareto, Joanna Fowler, Anat Biegon
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Transcript of J Logan,Yu-Shin Ding, Kuo-Shyan Lin, Deborah Pareto, Joanna Fowler, Anat Biegon
Modeling and analysis of PET studies with norepinephrine transporter (NET) ligands: The search for a reference
region
J Logan,Yu-Shin Ding, Kuo-Shyan Lin, Deborah Pareto, Joanna Fowler, Anat Biegon
Brookhaven National Laboratory
• Monoamine transporters remove neurotransmitters from synapse: SERT, DAT and NET
• Widespread distribution of NETs: thalamus, brain stem, cerebellum, frontal cortex,cingulate
• NET densities lower than DAT Bmax in basal ganglia
Problem:Many NET ligands exhibit a high and nonuniform (nonNET binding) which makes the identification of a reference region difficult.
The use of a reference region increases reproducibility of the outcome measure in test/retest studies
Why do we need a reference region?
NET tracers *(S,S)-[11C]-methyl reboxetine (SS-MRB)
(R,R)-[11C]-methyl reboxetine (RR-MRB)
[11C]-Nisoxetine (NIS)
(S,S)-[18F]fluororeboxetine (SS- FRB)
(R,R)-[18F]fluororeboxetine (RR- FRB)
Measured arterial input functions corrrected for metabolites
Methods:PET studies
Subjects (baboons): *Friendly, April, Chloe, Jess, Spicey
k6
NN
NETNS/FCp
K1
k2
k3
k4
k5
Model of NET ligand binding
2 1dROI k ROI K Cpdt
22 (1 )NN NET
kkBP BP
5 3
6 4
NN NETk kBP BPk k
1 2( / )(1 )NET NNDV K k Bp Bp
NET+ NN+NSCpK1
2k
wm occ bg tmp cng par cb fc mb thl
DV
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thalamus (thl) 9.62 ± 2.53 cerebellum (cb) 6.89 ± 1.79 cingulate gyrus (cng) 6.32 ± 1.35 basal ganglia (bg) 5.58 ± 1.31 occipital cortex (occ) 5.40 ± 1.20 frontal cortex (fc) 5.05 ± 1.36
Average DV for (S,S)-[11C]-MRB Baseline (n=18, 6 baboons)
0 2 4 6 8 10 12 14 16 18 20
DV
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16Friendly
AprilSpicey
Alecia
DaisyJess
thl
occ
Variation in DV between studies for thalamus and occipital cortex for SS-MRB
Study number
Why a reference region is needed
Blocking experiment to identify reference region
Experimental: PET studies with SS-MRB
(1)Baseline study
(2)Pretreat with cocaine (0.2, 0.4 or 0.8 mg/kg 5 minutes prior to the injection of the tracer
Cocaine is a non-selective inhibitor of DAT, SERT and NET
Reboxetine is a specific NET inhibitor with a high affinity and high selectivity
wm occ bg tmp cng par cb fc mb thl stm
% c
hg in
DV
with
Coc
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wm occ bg tmp cng par cb fc mb thl stm
% c
hg in
DV
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wm occ bg tmp cng par cb fc mb thl stm
% c
hg in
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coc
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% Change in DV of (S,S)-MRB after Pretreatment with Cocaine
a. % chg in DV with 0.2 mg cocaine n=4 b. % chg in DV with 0.4 mg cocaine n=3
c. % chg in DV with 0.8 mg cocaine n=4
basal ganglia (bg), occipital cortx(occ), frontal cortx (fc) thalamus (thl), midbrain (mb), brainstem (stm),
DV ratio bg/occ (n= 18) 1.03 0.096 Friendly 1.19 0.07 Jess 1.05 0.05 April 0.99 0.06 Spicey 0.93 0.02
Using the composite REF the coefficient of variation (CV) for thl was reduced from 0.25 for the DV to 0.14 for the DVR
Smallest changes occurred in bg and occ for cocaine doses of .4 and .8 mg/kg
Observations
Reference region: (bg+occ)/2
Average DVR for (S,S)-[11C]-MRB Baseline (n=18)
REF=(occ+bg)/2
wm occ bg tmp cng par cb fc mb thl
DVR
0
1
2thl 1.76 ± 0.24 cb 1.28 ± 0.10 cng 1.16 ± 0.14 bg 1.01 ± 0.05 occ 0.98 ± 0.06 fc 0.92 ± 0.14
occ bg tmp cng par cb fc mb thl
DVR
0
1
2 SS mean (n = 7) RR mean (n = 2)
(SS RR) MRB SS MRB Pretreat with nisoxetine *
DVR for SS and RR MRB for “Friendly”
*nisoxetine binds a single class of saturable sites associated with NE uptake (Tejani-Butt, 1991)
occ bg tmp cng par cb fc mb thlD
VR0
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Baseline Pretreat
occ bg tmp cng par cb fc mb thl
DV
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SS DV (n=5)RR DV (n=1)
occ bg tmp cng par cb fc mb thl
DVR
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DVR SS (n=5)DVR RR (n=1)
Baseline DV and DVR for (S,S) and (R,R) [18F]-FRB
occ bg tmp cng par cb fc th
DV
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occ bg tmp cng par cb fc thl
DVR
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DV DVR (occ+bg)/2
Baseline DV and DVR for [11C]-NIS
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1 S NNT T
KDV Bp Bpk
1
2
1 NNREF REF
KDV Bpk
Target Reference
(1 ) 1 /(1 )(1 )
NNNET NNT T
TNNREF REF
DV BpDVR Bp BpDV Bp
Summary(1)Large variation in DV of SS-MRB for a single baboon.
Reduced by using a reference region => a major source of variability is global, common to both regions and cancels in the ratio.
(2)The use of the avg of BG and OCC appeared to be better than either one alone to compensate for individual differences.
(3) NN binding varies with ligand. SS-MRB better than NIS or FRB. NIS pretreatment in SS MRB study did not appear to alter NN binding but reduced NET binding resulting in binding profile like the RR MRB cmpd
(4)Advantages of SS-MRB (a) Lower NN binding (b) Kinetics permit DV determination with 11C label
Brookhaven Center for Translational Neuroimaging
Funded by DOE-OBER, NIH and ONDCP
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