DOE Animal Imaging Meeting May 20, 2004 Martin G. Pomper Johns Hopkins University Imaging Awake...
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Transcript of DOE Animal Imaging Meeting May 20, 2004 Martin G. Pomper Johns Hopkins University Imaging Awake...
DOE Animal Imaging Meeting May 20, 2004
Martin G. PomperJohns Hopkins University
Imaging Awake AnimalsImaging Awake Animals
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
Ben Tsui
Venu Raman
Ron Mease
SAIRP: structure
Current, active collaborators
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)AstraZenecaGlaxoWellcome
Inside Outside
New antibody-based imaging agents
Molecular target
[131I]anti-TEM7 tumor endothelium [125I]anti-claudin 4 pancreatic carcinoma [125I]anti-PSCA pancreatic carcinoma New cellular imaging agent
[125I]C. novyi spores C. novyi Conventional agents
[64Cu]ATSM hypoxia [64Cu]PTSM perfusion [18F]KF bone [15O]H2O perfusion [125I]anti-CD20 lymphocytes [131I]anti-CEA colon cancer [99m Tc]annexin V phosphatidyl serine (apoptosis) [125I]FIAU HSV1-TK [11C]raclopride * D2-dopamine receptors [11C]PK111 95* PBBR (inflammation) [11C]WIN 35,428 * dopamine transporters [11C]carfentanil * μ- opioid receptors [18 ]F fluorodeoxyglucose glucose metabolism * ( , , , )PET Center Dannals Ravert Mathews Smoot
Radiopharmaceutical synthesis: JHU SAIRP
Radiopharmaceutical synthesis: JHU SAIRP
New Receptor-based radiotracers
Molecular target
[11C]DCMC glutamate carboxypeptidase II [125I]ZJ-17 glutamate carboxypeptidase II [11C]GW7845 PPARγ [11 ]C AR - 26500R α7- nicotinic cholinergic receptor [11 ]C AR - 27159R α7- nicotinic cholinergic receptor [125 ]I AR- 26855R α7- nicotinic cholinergic receptor [125 ]I AR- 27184R α7- nicotinic cholinergic receptor [125 ]I phos-FLAG cell surface azidosugars [11 ]C paclitaxel P-glycoprotein ([18 ] 665017)F M α7- nicotinic cholinergic receptor ([18 ] )F FBnDCMC glutamate carboxy peptidase II
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
Why anesthesia in imaging?
decrease motion artifact (especially for functional MR imaging)
decrease pain and stress?
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
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
Effects of anesthesia on cerebral blood flow
anesthetic effect on CBF
isoflurane ↑↑chlor al hydrate =α-chloralose ↓propofol ↓se vofl urane ↓pentobarbital ↓↓
Reversal of rCBF responses due to levodopa
(Hershey T, et al., Exp Neurol 2000;
166:342)
Magnitude vs. increment in functionalbrain imaging
(Shulman RG, et al. PNAS 1999; 96:3245)
Anesthetic and dosage effectOn rCBF in humans by SPM
(Kaisti K, et al. Anesthesiology2002; 96:1358)
Task
BrainElectricalResponse
fMRI Data
??
??
Isoflurane: increases rCBF but decreases metabolism
FDG in awake rats: state-of-the-art
(Kornblum, et al. Nat Med 2000; 18:655)
(Clin Pharm 2001; 41:64S)
Extracellular dopamine assessed with PET
TYROSINE
DA
DOPA
DA
DA
DA
MAO
DOPAC
DA
TYROSINE
DA
DOPA
DA
DA
DA
MAO
DOPAC
DA
DADA DA DA
DA
DADAmethylphenidate
CONHCH2
ClCl
O11CH3HO
NC2H5
H
[11C]raclopride
CONHCH2
ClCl
O11CH3HO
NC2H5
H
[11C]raclopride
RRRRRR
(Courtesy: Joanna Fowler, BNL)
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):
RO% = 100 *
BP0 - BPdrug
BP0
Ca Cf Cbk2
K1 k3
k4
Anesthesia effects on receptor-basedimaging: 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)
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}
Anesthesia effects on receptor-basedimaging: dopaminergic transmission
(Ginovart N, et al., Neuropsychopharmacology 2002; 27:72)
11C-Raclopride for D2DR in rat striatum
Transaxial
Coronal
High specific activity study
Blocking study(1 mg/kg cold RAC)
0
50
100
150
200
250
300
350
400
450
500
0 10 20 30 40 50 60
StriatumCortex
time (min)A
vera
ge
cou
nts/
pixe
l
Time-activity curves from HSA studyTime-activity curves from HSA study
Time (min)
(Jae Sung Lee)
isoflurane and sevoflurane inhibit agonist binding to nAChRs
propafol reduces mAChR availability (by 11C-methyl-benztropine PET) to mediate unconsciousness
Anesthesia effects on receptor-basedimaging: other receptor systems
11C-NMPYB can measure increased endogenous brain ACh levels after phenserine (AChE inhibitor) treatment
Imaging AChE inhibition with small animalPET: a cautionary tale
(Ma B, et al., Nucl Med Biol 2004; 31:393)
Imaging AChE inhibition with small animalPET: a cautionary tale
The brain isn’t everything
(Toyama H, et al. Nucl Med Biol 2004; 31:251)
(Yang X-P, et al. Heart Circ Physiol 1999; 46:H1967-H1974)
echocardiography
ATLAS small animal PET
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