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DOE Animal Imaging Meeting May 20, 2004

Imaging Awake Animals. Martin G. Pomper Johns Hopkins University. DOE Animal Imaging Meeting May 20, 2004. Utility of small animal imaging. longitudinal studies – own control fewer, readily available animals (rodents) transgenic and other models of human disease

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DOE Animal Imaging Meeting May 20, 2004

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  1. Imaging Awake Animals Martin G. Pomper Johns Hopkins University DOE Animal Imaging Meeting May 20, 2004

  2. Utility of small animal imaging longitudinal studies – own control fewer, readily available animals (rodents) transgenic and other models of human disease dedicated systems: no competition with clinic more physiologically relevant milieu to study systems, e.g., protein-protein interaction, gene expression

  3. Ben Tsui Ron Mease Venu Raman SAIRP: structure

  4. Inside Outside Hyam Levitsky (oncology) T-C Wu (pathology) Bert Vogelstein (oncology) Richard Ambinder (oncology) John Laterra (oncology, KKI) Chi Dang (hematology) Edward Gabrielson (pathology) Kathleen Gabrielson (comparative med.) Manuel Hidalgo (oncology) Pete Pederson (biological chemistry) Kwamena Baidoo (SPH - radiochemistry) Tom Guilarte (SPH - toxicology) Srinivasa Raja (neurology) Jun Liu (pharmacology) Jin Zhang (pharmacology) Linzhao Cheng (ICE) Ron Rodriguez (urology) Drew Weisenberger (Jefferson Natl. Labs) Carolyn Bertozzi (Univ. California, Berkeley) Stan Majewski (Jefferson Natl. Labs) Mark Williams (Univ. Virginia) Juri Gelovani (MD Anderson Cancer Center) Steve Michnick (Univ. of Montreal) Alan Kozikowski (Univ. Illinois, Chicago) AstraZeneca GlaxoWellcome Current, active collaborators

  5. Radiopharmaceutical synthesis: JHU SAIRP

  6. Radiopharmaceutical synthesis: JHU SAIRP

  7. What is anesthesia? • change in bilayer properties (Meyer-Overton) • receptor-mediated phenomena: • inhibition of currents in excitatory ligand gated ion channels (LGICs) • excitation of inhibitory channels • receptor desensitization by neurotransmitters in membranes

  8. Why anesthesia in imaging? decrease motion artifact (especially for functional MR imaging) decrease pain and stress?

  9. Indications for awake imaging avoid influence of anesthesia on: blood flow, metabolism, neural-vascular coupling elucidate disease pathophysiology drug/radiopharmaceutical development mimic the human state

  10. Effects of anesthesia: brain blood flow/metabolism effects depend on the dose and type of anesthetic used cerebrovascular reactivity to CO2 is perturbed by anesthetics suppression of neural activity how is global vs. regional CBF modulated by anesthetics? species/strains have different sensitivities to anesthesia

  11. Effects of anesthesia on cerebral blood flow

  12. Reversal of rCBF responses due to levodopa (Hershey T, et al., Exp Neurol 2000; 166:342)

  13. Magnitude vs. increment in functional brain imaging (Shulman RG, et al. PNAS 1999; 96:3245)

  14. Anesthetic and dosage effect On rCBF in humans by SPM (Kaisti K, et al. Anesthesiology 2002; 96:1358)

  15. Isoflurane: increases rCBF but decreases metabolism Task ?? Brain Electrical Response ?? fMRI Data

  16. FDG in awake rats: state-of-the-art (Kornblum, et al. Nat Med 2000; 18:655)

  17. (Clin Pharm 2001; 41:64S)

  18. M A O M A O H C O N H C H 2 N C H 2 5 1 1 H O O C H 3 H C O N H C H 2 N C l C l C H 2 5 1 1 H O 1 1 O C H 3 [ C ] r a c l o p r i d e C l C l 1 1 [ C ] r a c l o p r i d e Extracellular dopamine assessed with PET T Y R O S I N E T Y R O S I N E D O P A D O P A D A D A D A D A D O P A C D A D O P A C D A D A D A D A D A m e t h y l p h e n i d a t e D A D A D A D A R D A D A R R D A R R R (Courtesy: Joanna Fowler, BNL)

  19. Receptor occupancy: dose finding • generate time-activity curves (TACs) over ROIs, e.g., cortex and cerebellum • apply an appropriate model to the TAC data: • generate receptor occupancy (RO) from the model parameters using binding potentials estimated at baseline (BP0) and after administering drug (BPdrug): K k 1 3 C C C a f b k k 2 4 BP0 -BPdrug BP0 RO% = 100 *

  20. Anesthesia effects on receptor-based imaging: dopaminergic transmission augmentation of increased DA by cocaine or GBR12909 (DAT) by isoflurane cocaine had no effect on 11C-raclopride (D2DR) binding in the awake state Explanation: isoflurane enhances NO synthesis (induced by glu transmission and production of NOS) – NO facilitates uptake of DA transporter ligands by DAT Conclusion: indirect effects between isoflurane and DAT inhibitors must be taken into account (Tsukada H, et al., Brain Res 1999; 849:85)

  21. Anesthesia effects on receptor-based imaging: dopaminergic transmission decreased 11C-raclopride was demonstrated after amphetamine under ketamine but not under halothane Explanation: halothane promotes conversion of D2 receptors to a low-affinity state (for DA) Question: is 11C-raclopride binding a) increased under halothane, b) decreased under ketamine or c) both? {Answer: need to do awake imaging study} (Ginovart N, et al., Neuropsychopharmacology 2002; 27:72)

  22. Time-activity curves from HSA study 500 450 400 Striatum 350 Cortex 300 250 Average counts/pixel 200 150 100 50 0 0 10 20 30 40 50 60 time (min) 11C-Raclopride for D2DR in rat striatum High specific activity study Blocking study (1 mg/kg cold RAC) Time-activity curves from HSA study Transaxial Time (min) Coronal (Jae Sung Lee)

  23. Anesthesia effects on receptor-based imaging: other receptor systems isoflurane and sevoflurane inhibit agonist binding to nAChRs propafol reduces mAChR availability (by 11C-methyl- benztropine PET) to mediate unconsciousness

  24. Imaging AChE inhibition with small animal PET: a cautionary tale 11C-NMPYB can measure increased endogenous brain ACh levels after phenserine (AChE inhibitor) treatment (Ma B, et al., Nucl Med Biol 2004; 31:393)

  25. Imaging AChE inhibition with small animal PET: a cautionary tale

  26. echocardiography ATLAS small animal PET (Toyama H, et al. Nucl Med Biol 2004; 31:251) (Yang X-P, et al. Heart Circ Physiol 1999; 46:H1967-H1974) The brain isn’t everything

  27. Conclusions Anesthesia has varied and often inconsistent effects on physiology not only inherently, but also due to inter-institutional differences in administration. Those effects are dose, species and strain dependent. The mechanism of action of various anesthetics, not to mention the effects on physiology, are poorly characterized. Awake animal, including small animal, imaging is feasible for a number of modalities and can eliminate this confound. CA 92871

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