boosting the sensitivity of nuclear magnetic resonance hyperpolarized mri yves de deene
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Boosting the sensitivity of
nuclear magnetic resonance
Hyperpolarized MRI
Yves De Deene
2/15s
2/15p
2/35p
0B0 0B0
1/2m1/2
1/2m1/2
1/2m1/2
1/2m1/2
)1( jm
In this presentation ...
The future of hyperpolarized Xe129
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MRI: Basic principles
Hyperpolarized gas MRI
Molecular imaging with MRI
I.I. Rabi1938
E. Purcell1946
F. Bloch1946
Superconducting coil (magnet)
Radiofrequency coil
Gradient coil
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The use of MRI: basic principle
The advantage of magnetic resonance imaging (MRI) is the absence of any ionizing irradiation to acquire an image.
To make an MRI image use is made of a static magnetic field, radiofrequency waves (electromagnetic waves similar to the ones received by a transistor radio) and switched magnetic fields (gradients).
No adverse health effects are found with the use of MRI scanners.
Unlike any other medical imaging modality, it are the (nuclei of atoms within) molecules themselves that are the signal carriers.
The molecular interactions of water molecules with macromolecular structures (proteins, cell membranes, etc.) are responsible for the image contrast.
The superior soft tissue contrast originates from the large amount of water molecules that ‘probe’ the cellular microstructure. The water molecules interact with cellular components through diffusion, collision, adhesion, absorption, collision, chemical exchange and magnetization transfer. All these interactions cause changes in the behavior of the received MR signal.
The use of MRI: basic principle
Conventional magnetic resonance imaging (MRI) is based on the radiofrequency signal that is transmitted from the atomic nucleus of hydrogen atoms placed in a magnetic field and after they have been excited by a radiofrequent electromagnetic pulse.
Cross-section of an NMR scanner
Water molecule
Hydrogen proton has a magnetic moment
external magnetic field
Cryogenic magnet
Radiofrequency coil
Gradient coil
Hydrogen proton transmits a radiofrequent electromagnetic wave (yellow) after excitation by an RF pulse (red)
The electromagnetic signal transmitted by the hydrogen protons is received by the scanner and processed...
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The contrast in NMR is based on the molecular physics of water molecules
(e.g. spin-spin relaxation)Pound PurcellBloembergen
INTERMEDIATELAYER
FREEWATER
Hydrogen bridges
C
C
OO
C N BOUNDLAYER
+
+ +
+
-
--
+
+
- - +
-
- +
++
+
Protein, polymer, cell membrane
M
M
M
t
t
t
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Low mobility
High mobility
k.T
E
1/2
1/2 eN
N
0BE ... hh
B0
-1/2
+1/2
2kTNN
NNP
1/21/2
1/21/2 h
100.000
110P 5
( at 3T )
Boltzmannstatistics
MOLECULAR IMAGING WITH MRILow sensitivity of conventional 1H MRI
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The sensitivity of conventional MRI is governed by Boltzman statistics. In a magnetic field of 3T, only an excess of one of 100,000 atoms is magnetized in the direction of the applied magnetic field.
MR contrast agent
Blood circulation (MRA)
NON SPECIFICCONTRAST AGENTS
Perfusion
SPECIFICCONTRAST AGENTS
Reporter
Ligand
Vector Receptor(Target)
• Cell receptor• Gene sequence• Enzyme
MOLECULAR IMAGING WITH MRIExogeneous contrast agents
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ESSENTIAL PROPERTIES
SENSITIVITY
In vivo moleculaire doelwitten:1 nM – 1 pM
MolecularContrast = Foreground Background-
BIO DISTRIBUTION(Pharmacokinetics)
BIO COMPATIBILITYSPECIFICITY
MOLECULAR IMAGING WITH MRIMolecular specific probes
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HYDRATIONSPHERE
Gd3+
Gd3+
Gd3+
Gd3+
Gd3+
Gd3+
Gd3+
Gd3+
Gd3+
MOLECULAR IMAGING WITH MRIThe sensitivity problem: molecular specific probes
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PEG
Gd-DTPA lipid
Antibody
phospholipide
phospholipid
contrastagent
Perfluoro-octylbromide nanoparticle
Lecithine/cholesterol
Gd-DTPA-PE
Biotinylated DPPE
antibody
avidin
Liposomes / Micelles Magnetic nanoparticles
FexOy
vector
vector
(Ultra-)Small-Particle Iron-OxideSPIO, USPIO
Size: 30 nm - 300 nmr1 ≈ 25 s-1.mM-1
MOLECULAR IMAGING WITH MRIIncreasing sensitivity by increasing the number of reporter molecules
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H2O
Liposome membrane
T
Temperature sensitive contrastagent
CLIO
Gen-sequence specific contrastagent
Enzym-mediated contrast agent
β-galactosidase
Ca2+ mediated contrastagent
(also for Zn2+ en pH)
« Switch-on / switch-off » probes
MOLECULAR IMAGING WITH MRI‘Smart’ contrastagents
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Perfluoro-octylbromide nanoparticle
Lecithine/cholesterol
Gd-DTPA-PE
anti αvβ3 - integrine
Artherosclerose
MOLECULAR IMAGING WITH MRIIn vivo experiments
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SENSITIVITY ENHANCEMENT WITHBIGGER CONTRAST AGENTS
Loss of specificity
Disturbance of the de pharmacokinetics
MOLECULAR IMAGING WITH MRIDilemma for molecular imaging with 1H paramagnetic contrastagents
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X-ray
PET
1 μm 10 μm 100 μm 1 mm 1 cm 1 dm
1 mM
1 μM
1 nM
1 pM
MRI
Spatial resolution
Sensitivity
In vivomolecular targets
SPECT
MRS
MRI (‘pushing the limits’)
MOLECULAR IMAGINGIncreasing the sensitivity of MRI
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HYPERPOLARISATION OUTSIDE THE SCANNER
% 50P
INJECTION OF HYPERPOLARIZED
AGENT
SCANNING THE PATIENT
MOLECULAR IMAGING WITH MRIHYPERPOLARIZATION:
A possible alternative for boosting NMR sensitivity
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Parahydrogen
13C
B0
‘Brute Force’
cooling
roomtemperature
(P = 10-5)
DynamicNuclearPolarization
94 GHz
13C
Optical pumping
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How to obtain HYPERPOLARIZATION ?
Hyperpolarized gas NMR by optical pumping
Philips G.C., Perry R.R., Windham P.M.,“Demonstration of a Polarized He3 Target for Nuclear Reactions”Physical Review Letters, 9, 502-504, 1962.
Bouchiat M.A., Carver T.R. And Varnum C.M.“Nuclear Polarization in He3 Gas Induced by Optical Pumping and Dipolar Exchange”Physical Review Letters, 5, 373-375, 1960.
Walters G.K., Colegrove F.D. and Schearer L.D.“Nuclear Polarization of He3 Gas by MetastabilityExchange with Optically Pumped Metastable He3 Atoms”, Physical Review Letters, 9, 502-504, 1962.
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1/2m1/2
1/2m1/2
1/2m1/2
1/2m1/2
Hyperfine structure
Hyperpolarized gas NMR by optical pumpingPrinciple
Rb
2/15s
2/15p
2/35p
)1( jm
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794.7 nm
Fine splitting
Hyperpolarized gases: Spin exchange
Rbplate
4
λ
Laser-beam
He3
OPTICALPUMPING
SPIN EXCHANGE
H = a(r).I.S
Hyperpolarized gas NMR by optical pumpingPrinciple: Electron energy states of Rubidium
Bohr model
1.56 eV
0l 5s
1l 5p
Fine structure
-310 eV
21 25 /s
21 25 /p
23 25 /p
1
2j
1
2j
3
2j
Hyperfinestructure
-610 eV
1F
2F
1F
2F
ZeemansplittingB
@ 1mT
-810 eV
101
10
1
2
2
1
01
1
0
1
2
2
Fm
I
e-J
F J I
n
e-
Hyperfine interaction(nucleus – angular momentum)
e-
e-
e-
L
S
J L S
Fine interaction(spin – orbital momentum coupling)
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1
0
1
1
0
1
21 25 /s
21 25 /p
1( )Fm
Hyperpolarized gas NMR by optical pumpingPrinciple: Optical pumping of Rubidium
photon (S = 1)
794 8. nm
e- e-
electron = trapped Fm
1.56 eV
0 0I.S. Is B z zA g S B I B
I
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N.S K.S I.S( ). ( ). .Rb Xe R R A
2Rb Fe
eg F
m
Hyperpolarized gas NMR by optical pumpingRubidium-Xenon Spin-Exchange
L
S
I
F
N
K
Rb Xe
Spin rotationHyperfine coupling
(Rb electron – Xe nucleus)Hyperfine coupling
(Rb)
( ) ( ) ( ) ( )Rb Xe Rb Xe
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Hyperpolarization generator
Opticalspectrometer
Polarisation optics
Laser powermeter
Circulation bathoil (~ 140 °C)
Oil bath(~ 140 °C)
Glass cell(Xe-129, N2, He)
Pinhole
Semi-transparantmirror
Circulation bath(cooling liquid)
Laser unit
NMR-acquisition
Vacuumpump
ToSpectrometer
or scanner
Xe-129
HeN2
Rb
Coil for static magnetic field (~ 5 mT)
Pre amplifier
PA100 W
Cooling circuit
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Hyperpolarized gases: Spin exchange
T1
PP).(P
dt
dPRbSE
• Rb density• collision rate
SE
C)157(T/ml101.47[Rb] 14
1SE h0.125
Example:
t [h]P
olar
izat
ion
0
0.2
0.4
0.6
0.8
2.5 h
5 h
10 h
33 h
5 h 10 h
T1
15 h0 h
From: Leawoods et al, Concepts in Magnetic Resonance, 13(5): 277-293, (2001).
Hyperpolarized gases: Sequences and Applications
In H1-imaging: T1 is needed for recovery of signal
In Xe129-imaging: All imaging has to be performed within a time T1
Small flip angles should be used (FLASH, FISP)
• Static He3 density images (during breath-hold)• Diffusion images (Optimized Interleaved-Spiral): Restricted diffusion by alveolar walls (emphysema)
• Xe129 transport into tissue (Compartimental analysis)
• He3 and Xe129 Spectroscopy
• Tagging for monitoring lung ventilation
• Dynamic studies with EPI sequences25/33
Dynamic MRI of the lung
SOURCE: University of Virginia Health Systems
MR ventilation images of the lung asthma studies with He-3 Hyperpolarized
Xe-129 imaging
3D rendered MRI of the lung
HYPERPOLARISED GAS NMR:Some immediate applications
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HYPERPOLARISED GAS NMR:Lung imaging
20-year oldnon-smoker
62-year oldsmoker
Diffusion imaging reveals lung microstructure
Inhalation Exhalation Displacement vectors
Cai et al, Int. J. Radiation Oncology Biol. Phys. 68, 650-3, 2007Fain et al, J. Magn. Reson. Imaging. 25, 910-23, 2007
Tagging reveals lung motion
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HYPERPOLARISED GAS NMR:No need for high-field strength scanners ...
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Mag
netic
spi
n p
olar
izat
ion
T1
T1-decay
t60 s
Injection
T1 relaxation decay is determined by
the Intra-molecular environment
the solvent
the temperature
the degree of acidity (pH)
T1 3He 129Xe
pure gas months 21 days
in Pyrex test tube 2 h – 30 h 20 min
In vivo 30 s – 60 s 20 s – 40 s
HYPERPOLARISED GASDecay time
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Polairpeptide
Cryptophane-Acage
polar peptidebiotin
Not bound
bound
SOURCE: Spence MM et al 2001, PNAS 98, 10654-7
NMR spectrumMolecular probe
Xe-129 as a smart molecular contrast agent spectrum
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HYPERPOLARISED Xe-129as a molecular marker
Science 314: 446-9, 2006
T1
M
t
The problem
Loss of magnetization before tracer at site
T1Xe
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HYPERPOLARISED Xe-129as a molecular marker
Hyperpolarized Xe-129
50 ppm200 ppm 100 ppm100 ppm
Chemical shift
CHEMICAL EXCHANGE
Schröder et al, Science 314: 446-9, 2006 32/33
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Hyperpolarized gases: Objectives of the UGent research group
Construction of a hyperpolarizer for Xe129 MRI
Implementation of clinical applications for pneumology / oncology
Investigation of the possible use of hyperpolarized MRI for molecular imaging
Hyperpolarization of other nuclei (SPINOE)
I visited Copenhagen frequently after the war. At one point, I gave a talk in Copenhagen, and then afterwards we met with Bjerrum. Bjerrum was a chemist and a great friend of Niels Bohr… Bohr said to him: “You know, what these people do is really very clever. They put little spies into the molecules and send radio signals to them, and they have to radio back what they are seeing.” I thought that was a very nice way of formulating it. That was exactly how they were used. It was not anymore the protons as such. But from the way they reacted, you wanted to know in what kind of environment they are, just like spies that you send out. That was a nice formulation.
- Felix Bloch -