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 -