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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.

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J Logan,Yu-Shin Ding, Kuo-Shyan Lin, Deborah Pareto, Joanna Fowler, Anat Biegon

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  1. 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

  2. Monoamine transporters remove neurotransmitters from synapse: SERT, DAT and NET • Widespread distribution of NETs: thalamus, brain stem, cerebellum, frontal cortex,cingulate • NET densitieslower than DAT Bmax in basal ganglia

  3. Problem: Many NET ligands exhibit a high and nonuniform (nonNET binding) which makes the identification of a reference region difficult. Why do we need a reference region? The use of a reference region increases reproducibility of the outcome measure in test/retest studies

  4. Methods: PET studies Subjects (baboons): *Friendly, April, Chloe, Jess, Spicey 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

  5. K1 NET+ NN+NS NN Cp k6 NET NS/F Cp k5 K1 k3 k2 k4 Model of NET ligand binding

  6. Average DV for (S,S)-[11C]-MRB Baseline (n=18, 6 baboons) 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

  7. Friendly Spicey April Alecia Daisy Jess thl occ Why a reference region is needed Variation in DV between studies for thalamus and occipital cortex for SS-MRB Study number

  8. Blocking experiment to identify reference region • Experimental:PET studies with SS-MRB • Baseline study • 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

  9. % 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 basal ganglia (bg), occipital cortx(occ), frontal cortx (fc) thalamus (thl), midbrain (mb), brainstem (stm), c. % chg in DV with 0.8 mg cocaine n=4

  10. Observations Smallest changes occurred in bg and occ for cocaine doses of .4 and .8 mg/kg Reference region: (bg+occ)/2 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

  11. Average DVR for (S,S)-[11C]-MRB Baseline (n=18) REF=(occ+bg)/2 thl 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

  12. 2 Baseline Pretreat DVR 1 0 occ bg tmp cng par cb fc mb thl DVR for SS and RR MRB for “Friendly” (SS RR) MRB SS MRB Pretreat with nisoxetine * *nisoxetine binds a single class of saturable sites associated with NE uptake (Tejani-Butt, 1991)

  13. Baseline DV and DVR for (S,S) and (R,R) [18F]-FRB

  14. Baseline DV and DVR for [11C]-NIS DV DVR (occ+bg)/2

  15. Reference Target

  16. Summary • 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. • The use of the avg of BG and OCC appeared to be better than either one alone to compensate for individual differences. • 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 • Advantages of SS-MRB (a) Lower NN binding (b) Kinetics permit DV determination with 11C label

  17. 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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