1. Boosting the sensitivity of nuclear magnetic resonance
Hyperpolarized MRI
Boosting the sensitivity of
nuclear magnetic resonance
Yves De Deene

2. In this presentation ... MRI: Basic principles
Molecular imaging with MRI
Hyperpolarized gas MRI
The future of hyperpolarized Xe129
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3. The use of MRI: basic principle
I.I. Rabi
1938
E. Purcell
1946
F. Bloch
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.
Superconducting
coil (magnet)
Radiofrequency
coil
Gradient coil
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.
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4. 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.
Hydrogen proton
has a magnetic moment
external
magnetic field
Cryogenic magnet
Radiofrequency coil
Gradient coil
Water molecule
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...
Cross-section of an NMR scanner
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5. The contrast in NMR is based on
Pound
Purcell
Bloembergen
The contrast in NMR is based on
the molecular physics of water molecules
(e.g. spin-spin relaxation)
FREE
WATER
Hydrogen bridges M t
High mobility
INTERMEDIATE
LAYER
BOUND
LAYER + - C O N - +
Protein, polymer, cell membrane
Low mobility
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6. MOLECULAR IMAGING WITH MRI
Low sensitivity of conventional 1H MRI
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. B0
-1/2
+1/2
Boltzmann
statistics
( at 3T )
Bij het ondersheiden van exogene contraststoffen in magnetische resonantie beeldvorming is het belangrijk om een goed begrip te hebben van de fysische beperkingen. Omwille van de eenvoud in deze uiteenzetting werd bij de eerste dias verteld dat de staafmagneetjes gericht werden volgens het extern magnetisch veld. Dit kan verkeerdelijk de indruk gewekt hebben dat de magnetische dipoolmomenten van de atoomkernen gericht werden. In werkelijkheid zijn er in een extern magnetisch veld zoals dat van onze MR-scanner (3T) slechts één op atoomkernen die deelnemen aan dit proces. Gezien de grote hoeveelheid aan watersofkernen in menselijk weefsel is dit voldoende om aanleiding te geven tot een meetbaar signaal. In het licht van contraststoffen die in kleinere hoeveelheden geïnjecteerd worden is het echter wel belangrijk om deze fysische beperking in gedachten te houden.
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7. MOLECULAR IMAGING WITH MRI
Exogeneous contrast agents
MR contrast agent
Blood circulation (MRA)
NON SPECIFIC
CONTRAST AGENTS
Perfusion
SPECIFIC
CONTRAST AGENTS
Reporter
Ligand
Vector
Receptor
(Target)
Cell receptor
Gene sequence
Enzyme
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8. MOLECULAR IMAGING WITH MRI
Molecular specific probes
ESSENTIAL PROPERTIES
SENSITIVITY
SPECIFICITY
BIO DISTRIBUTION
(Pharmacokinetics)
BIO COMPATIBILITY
In vivo moleculaire doelwitten:
1 nM – 1 pM
Molecular
Contrast - =
Foreground
Background
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9. MOLECULAR IMAGING WITH MRI
The sensitivity problem: molecular specific probes
Gd3+
HYDRATION
SPHERE t
Gd3+
Hier wordt dit dilemma van de sensitiviteit geschetst in het licht van een Gadolinium-houdende paramagnetische contraststof. In het meest gunstige geval wordt slechts één op de atoomkernen beïnvloed door de magnetische veldverstoring van een Gadolinium-atoom.
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10. MOLECULAR IMAGING WITH MRI
Increasing sensitivity by increasing the number of reporter molecules
Liposomes / Micelles
Magnetic nanoparticles
contrastagent
FexOy
vector
Lecithine/cholesterol
Perfluoro-
octylbromide
nanoparticle
phospholipid
Gd-DTPA lipid
Gd-DTPA-PE
phospholipide
Biotinylated DPPE
avidin
(Ultra-)Small-Particle Iron-Oxide
SPIO, USPIO
Size: 30 nm nm
r1 ≈ 25 s-1.mM-1
PEG
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antibody
Antibody

11. MOLECULAR IMAGING WITH MRI ‘Smart’ contrastagents
H2O
Enzym-mediated contrast agent
β-galactosidase T
« Switch-on / switch-off »
probes
Liposome membrane
Temperature sensitive contrastagent
Ca2+ mediated contrastagent
(also for Zn2+ en pH)
CLIO
Gen-sequence specific contrastagent
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12. MOLECULAR IMAGING WITH MRI
In vivo experiments
Artherosclerose
Perfluoro-
octylbromide
nanoparticle
Lecithine/cholesterol
Gd-DTPA-PE
anti αvβ3 - integrine
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13. MOLECULAR IMAGING WITH MRI
Dilemma for molecular imaging with 1H paramagnetic contrastagents
SENSITIVITY ENHANCEMENT WITH
BIGGER CONTRAST AGENTS
Loss of specificity
Disturbance of the
de pharmacokinetics
In het geval van moleculair-specifieke paramagnetische contraststoffen botst men hierdoor al vlug op een beperking. Aangezien specifieke cel-receptoren (binding-sites) slechts in kleinere getale aanwezig zijn dient elke contrastmolecule honderden tot duizenden metaalatomen te bevatten om de kans te verhogen dat naburige watersofatoomkernen de interactie zouden waarnemen. Dit betekent echter dat deze contrastmoleculen heel groot worden waardoor hun interactie met de receptor in het gedrang komt en tevens minder permeabel worden om de bloedvaten te verlaten. Door de intrinsieke fysische beperkingen houdt de toename van de sensitiviteit (door meerdere metaalatomen in dezelfde contrastmolecule aan te brengen) een reductie van de specificiteit in (doordat de molecule ‘te’ groot wordt).
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14. Increasing the sensitivity of MRI
MOLECULAR IMAGING
Increasing the sensitivity of MRI
Sensitivity
1 pM
PET
In vivo
molecular
targets
1 nM
SPECT
1 μM
MRI (‘pushing the limits’)
MRI
De verschillende beeldvormingstechnieken die op niet-invasieve wijze biologisch weefsel in beeld kunnen brengen ingedeeld volgens ruimtelijke resolutie (abscis) en hun sensitiviteit (ordinaal). In vivo moleculaire doelwitten (zoals celreceptoren en eiwitten) komen in menselijk weefsel in concentraties voor kleiner dan 10^-9 Molair (1 nM). Met behulp van X-stralen kunnen microscopisch kleine structuren worden waargenomen maar het moleculair contrast is eerder beperkt. Nucleaire beeldvormingstechnieken (SPECT en PET) zijn gekenmerkt door een hoge sensitiviteit maar zijn intrinsiek beperkt in resolutie door de diffusie van het radioactief agens. Fluoroptische technieken kunnen aangewend worden in proefdieren maar door de beperkte indringdiepte in het zichtbaar lichtspectrum komen deze methoden niet in aanmerking voor in vivo beeldvorming van humane subjecten. Met behulp van nucleaire magnetische resonantie beeldvorming (MRI) kan een aanzienlijke beeldresolutie bekomen worden maar leent zich op het eerste zicht niet tot moleculaire beeldvorming door de relatief lage sensitiviteit.
Verder in deze presentatie zal verduidelijkt worden hoe de sensitiviteit van NMR beeldvorming toch kan worden opgedreven.
MRS
1 mM
X-ray
1 μm
10 μm
100 μm
1 mm
1 cm
1 dm
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Spatial resolution

15. MOLECULAR IMAGING WITH MRI
HYPERPOLARIZATION:
A possible alternative for boosting NMR sensitivity
HYPERPOLARISATION
OUTSIDE THE SCANNER
INJECTION OF
HYPERPOLARIZED
AGENT
SCANNING
THE PATIENT
Een uitweg uit deze impasse is het gebruik van een compleet ander mechanisme. In een aantal recente experimenten is men erin geslaagd om koolstof-13 atomen in een dergelijke toestand te brengen dat 50 % van de atoomkernen als staafmagneetjes zullen functioneren. Dit opent een immens potentiaal aan mogelijkheden voor moleculair-specifieke contraststoffen. In een speciaal toestel dat gebruik maakt van microgolven bij extreem lage temperaturen worden de koolstof-13 atomen buiten de scanner in een hypergepolariseerde toestand gebracht.
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16. How to obtain HYPERPOLARIZATION ?
‘Brute Force’ 
cooling
room
temperature
(P = 10-5)
Dynamic
Nuclear
Polarization
94 GHz
13C
Parahydrogen
13C B0
Optical pumping
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17. Hyperpolarized gas NMR by optical pumping
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, , 1960.
Philips G.C., Perry R.R., Windham P.M.,
“Demonstration of a Polarized He3 Target
for Nuclear Reactions”
Physical Review Letters, 9, , 1962.
Walters G.K., Colegrove F.D. and Schearer L.D.
“Nuclear Polarization of He3 Gas by Metastability
Exchange with Optically Pumped Metastable He3
Atoms”, Physical Review Letters, 9, , 1962.
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18. Hyperpolarized gas NMR by optical pumping Principle
Hyperfine structure Rb
Fine splitting
794.7 nm
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19. Hyperpolarized gases: Spin exchangeRb
He3
Laser-
beam
OPTICAL
PUMPING
SPIN
EXCHANGE
H = a(r).I.S

20. Hyperpolarized gas NMR by optical pumping Principle: Electron energy states of Rubidium
Fine structure
Hyperfine
structure e-
Fine interaction
(spin – orbital momentum coupling)
Zeeman
splitting B e- n
Hyperfine interaction
(nucleus – angular momentum)
Bohr model
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21. Hyperpolarized gas NMR by optical pumping Principle: Optical pumping of Rubidium
photon
(S = 1) e- e-
electron = trapped
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22. Hyperpolarized gas NMR by optical pumping Rubidium-Xenon Spin-Exchange
Hyperfine coupling
(Rb electron – Xe nucleus)
Hyperfine coupling
(Rb)
Spin rotation
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23. Hyperpolarization generator
Polarisation optics
Laser unit
Coil for static magnetic field (~ 5 mT)
Cooling
circuit
Glass cell
(Xe-129, N2, He)
Circulation bath
(cooling liquid)
NMR-acquisition
Pre amplifier PA
100 W To
Spectrometer or scanner Rb
Oil bath
(~ 140 °C)
Xe-129 He
Pinhole
Circulation bath
oil (~ 140 °C) N2
Optical
spectrometer
Laser power
meter
Vacuumpump
Semi-transparant
mirror
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24. Hyperpolarized gases: Spin exchange
t [h]
Polarization
0.2
0.4
0.6
0.8
2.5 h
5 h
10 h
33 h T1
15 h
0 h
Rb density
collision rate
Example:
From: Leawoods et al, Concepts in Magnetic Resonance, 13(5): , (2001).

25. 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 sequences
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26. HYPERPOLARISED GAS NMR: Some immediate applications
Dynamic MRI
of the lung
MR ventilation images of the lung
asthma studies with He-3
Hyperpolarized
Xe-129 imaging
3D rendered MRI
of the lung
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SOURCE: University of Virginia Health Systems

27. HYPERPOLARISED GAS NMR:
Lung imaging
Diffusion imaging reveals lung microstructure
Tagging reveals lung motion
20-year old
non-smoker
62-year old
smoker
Inhalation
Exhalation
Displacement
vectors
Fain et al, J. Magn. Reson. Imaging. 25, , 2007
Cai et al, Int. J. Radiation Oncology Biol. Phys. 68, 650-3, 2007
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28. HYPERPOLARISED GAS NMR: No need for high-field strength scanners ...
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29. HYPERPOLARISED GAS Decay time T1-decay t Injection 29/33 60 s T1 3He
T1 relaxation decay is determined by
T1-decay
the Intra-molecular environment
the solvent
Magnetic spin polarization
the temperature
the degree of acidity (pH)
60 s t
Injection 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
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30. Xe-129 as a smart molecular contrast agent
spectrum
Molecular probe
NMR spectrum
Polair
peptide
Cryptophane-A
cage
biotin
polar peptide
Not bound
bound
SOURCE: Spence MM et al 2001, PNAS 98,
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31. HYPERPOLARISED Xe-129 as a molecular marker The problem Xe T1
Loss of magnetization before tracer at site
Science 314: 446-9, 2006
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32. HYPERPOLARISED Xe-129 as a molecular marker 32/33
Hyperpolarized
Xe-129
CHEMICAL EXCHANGE
200 ppm
100 ppm
100 ppm
50 ppm
Chemical shift
Schröder et al, Science 314: 446-9, 2006
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33. 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)
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34. I visited Copenhagen frequently after the war
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 -