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CONTRAST AGENTS IN MRI

Lucie Paulet 15/07/2013
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Contents
1. A few definitions

2. Relaxation enhancing Contrast Agents

3. CEST Contrast Agents

4. Conclusion and Outlook

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A few definitions
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What is contrast?
In MRI: relative difference of the signal intensity
between two adjoining tissues.

One possible definition:

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What is a Contrast Agent?

Substance administered during MRI to:

Enhance natural contrast
Obtain dynamic information

NB: Unlike CAs in CT and Xray, indirect effect

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Why we need Contrast Agents

Early 1980s: first use of
Contrast Agents

Sometimes distinction
between region of interest
and evironment is
impossible:

signals are cancelled by

space averaging [1]
tissue properties too
similar
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Characteristics
Ability to modify some aspect of the observables/
tissue property involved in image contrast

Tissue specificity

Reasonable clearing period

Low toxicity and stability

Long Shelf Life

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Contrast Mechanisms in MRI

Difference of proton density (cannot be modified)

Modification of T1 or T2 relaxation times

Susceptibility effects (T2*)

Resonance Frequency Shifting

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(Current) Classification of Contrast Agents

Magnetic Properties Biodistribution
Paramagnetic

Extracellular

Superparamagnetic Intravascular (so called blood

pool contrast agents)

Tissue Specific
Diamagnetic (CEST)
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Relaxation enhancing CAs

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Modification of Relaxation Times

Relaxivity defines the quality of a CA

ri = (1/Ti)
[C]

Modification of relaxation rate

Ri = Ri0 + ri [C]
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How modifying Relaxation affects signal

intensity
Assuming SE sequence:

SI(C) = (1- exp ( -(R1 + r1C)TR)) exp(-(R2+r2C )TE)

Linear rise at low concentrations

saturation behaviour
T2 effects predominant at higher concentrations
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Paramagnetic Contrast Agents

Positive contrast (T1 enhanced)

Relaxation: to relax, water proton needs to

encounter fluctuating field

Without Contrast Agents, this means other

protons

But:
Melectron 700 Mproton
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Paramagnetic Contrast Agents

Paramagnetic materials:
Unpaired outer electrons dipoles

large field fluctuations

If close enough to the Larmor frequency,

relaxation of neighbouring protons significantly
modified

1/T1 = (1/T1)innersphere + (1/T1)outersphere

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Chemical Structure
Most paramagnetic
substances are toxic (i.e
Gadolinium)
Chelation to a ligand

Complex Binding is a
reversible process
Excess of free
compounds in case
toxic ions are released [2]
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Comparison of T1 and T2 weighted images,

with and without Contrast Agent

[3]
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Superparamagnetic Contrast Agents

Modify T2/T2* (negative contrast)

nanoparticles

Most common used compound: Iron Oxide

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Contrast Agent Nanoparticle

[4]
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How it works
Superparamagnetic compound induces very large
field inhomogeneities

Provoques dephasing of neighbouring protons

(susceptibility effects)

Decreases T2 (/T2*)
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Limits of Relaxation Enhancing CAs

Toxicity

Low specifity

Mostly exogenous affect bulk water relaxation

properties for contrast
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Chemical Exchange Saturation

Transfer Contrast Agents
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CEST Contrast Agents

Based on the notion of chemical shift

Works provided chemical exchange rate is in the

right regime

PARACEST and DiaCEST

Advantage of PARACEST: tissue contrast can be

turned on and off
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Chemical Saturation Transfer Imaging

Exogenous/endogenous compounds

Selective saturation of exchangeable protons or

molecules

Saturation is transfered through Chemical

Exchange

Indirectly detected through the water signal with

modified sensitivity
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2 Exchange Sites Model

[5]
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Limits of CEST CAs

B0 and B1 inhomogeneities, especially at high
magnetic fields

CEST pulse sequence: should be a long rectangular

pulse, but usually succession of gaussian pulses
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Other Contrast Agents

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Other Contrast Agents

Possibility of using X-ray Contrast Agents in MRI

Multispectral magnetic resonance imaging agents

Biodegradable Gadolinium Compounds

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Conclusion and Outlook

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Conclusion and Outlooks

We have seen
what contrast agents are
what main mechanisms are used today to design
them
The physics behind Contrast Agents will not
change
Progress to be made in the chemistry of contrast
agents
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Thank you for

your attention!
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References
General Concepts of Contrast Media
Papers :
[1] A. Sorensen, A. Tievsky, L. Ostergaard, R. Weisskoff, B. Rosen, "Contrast Agents in
Functional MR Imaging", January/February 1997; 7: 47-55
[2] W.R Bauer, K. Schulten, "Theory of Contrast Agents in Magnetic Resonance
Imaging", Magnetic Resonance in Medicine 1992; 26: 16-39
[3] H. Ersoy, F. Rybicki, M. Prince, "Contrast Agents for Cardiovascular MRI.", Contemporary
Cardiology: Cardiovascular Magnetic Resonance Imaging, : 237-253
[4] R. Heindricl, E. Haacke, "Basic Physics of MR Contrast Agents and Maximization of
Image Contrast.", JMRI 1993; 3: 137-148
[5] G. Yan, L. Robinson, P. Hogg, "Magnetic resonance imaging contrast agents: Overview
and perspectives", Radiography 2007; 13; e5-e9
Books:
[6] D. Weishaupt, V. D. Kchli, B. Marincek, How Does MRI Work? An Introduction to the
Physics and Function of Magnetic Resonance Imaging, second edition; Berlin, Springer,
2008
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Lecture Notes
[7]Atle Bjornerud, "The Physics of Magnetic Resonance Imaging", FYS-KJM 4740 Lecture Notes, march
2008

Videos
http://www.youtube.com/watch?v=Osx8Ced9Eyw

T2 and T1 Contrast Agents:

[8] C. Cunningham, T. Arai, P. Yang, M. McConnell, J. Pauly, S. Conolly, "Positive Contrast
Magnetic Resonance Imaging of Cells labeled with Magnetic Nanoparticles
[9] M. Woods, D. Woessner, A. Sherry, "Paramagnetic lanthanide complexes as PARACEST
agents for medical imaging", Chemical Society Reviews, April 11 2006
[10] R. Lauffer, "Paramagnetic Metal Complexes as Water Proton Relaxation Agents for
NMR Imaging: Theory and Design", Chem. Rev. 1997,87,901-927
[11] H. Bin Na, I. Song, T. Hyeon, "Inorganic Nanoparticles for MRI Contrast Agents",
Advanced materials, 2009, 21, 2133-2148
[12] S. Mornet, S. Vasseur, F. Grasset, E. DugMagnetic nanoparticle design for medical
diagnosis and therapyuet, "", Journal of Materials Chemistry, 2004,14,2161-2175
[13] J. Bulte, D. Kraitchman "Iron oxide MR contrast agents for molecular and cellular
imaging", NMR Biomed, 2004; 17; 484-499
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CEST Contrast Agents

[15] R. M Henkelman, G. J Stanisz, S. Graham "Magnetization transfer in MRI: a review",
NMR in Biomedicine, 2001; 14; 57-64
[16] A. Vinogradov, A. Sherry, R.Lenkinski, "CEST: From basic principles to applications,
challenges and opportunities", Journal of Magnetic Resonance, 2013, 229, 155-172
[17] F. Kogan, H. Hariharan, R. Reddy, "Chemical Exchange Saturation Transfer (CEST)
Imaging:Description of Technique and Potential Clinical Applications", Curr Radiol Rep; 14
February 2013; 1; 102-114
[18] K. Ward, A. Aletras, R. S Balaban, "A New Class of Contrast Agents for MRI Based on
Proton Chemical Exchange Dependent Saturation Transfer (CEST)", Journal of Magnetic
Resonance 2000; 143:79-87

Other Contrast Agents

[19] G. Zabow, A. Koretsky, J. Moreland, "Design and fabrication of a
micromachinedmultispectral
resonance imaging agent", J. Micromech. Microeng. 20 January 2009; 19
[20] S. Aime, L. Calabi, L. Biondi, M. Miranda, S. Ghelli, L. Paleari, C. Rebaudengo, E. Terreno,
"Ipamidol:
Exploring the Potential Use of a Well-Established X-Ray Contrast Agent for MRI", Magnetic
Resonance in Medicine 2005; 53: 830-834
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Image Credits
[1] V. Runge, Clinical MRI, Texas, W.B. Saunders Company
[2] http://www.google.de/imgres?q=gadolinium+chelate&um=1&client=ubuntu&sa=N&cha
nnel=fs&hl=en&biw=1303&bih=647&tbm=isch&tbnid=mg_2MAlsetAegM:&imgrefurl=htt
p://www.sepscience.com/Information/Archive/Featured-Articles/450-/IC-ICPMS-
Analysis-of-Gadolinium-based-MRI-Contrast-
Agents&docid=yiJhdkK40Ps4FM&imgurl=http://www.sepscience.com/images//Articles/I
ssues/1011/pFUNFSTEIN/Fig-
1.jpg&w=1468&h=568&ei=pZvjUf_SHoKitAaErIGQDA&zoom=1&iact=hc&vpx=169&vpy=
215&dur=786&hovh=139&hovw=361&tx=204&ty=53&page=1&tbnh=79&tbnw=200&start
=0&ndsp=18&ved=1t:429,r:1,s:0,i:85
[3 V. Runge, Clinical MRI, Texas, W.B. Saunders Company
[4] ] H. Bin Na, I. Song, T. Hyeon, "Inorganic Nanoparticles for MRI Contrast Agents", Advanced
materials, 2009, 21, 2133-2148
[5] F. Kogan, H. Hariharan, R. Reddy, "Chemical Exchange Saturation Transfer (CEST)
Imaging:Description of Technique and Potential Clinical Applications", Curr Radiol Rep; 14
February 2013; 1; 102-114