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UW-Madison Chemistry Department. Magnifying from inside: where a smart gadolinium unites chemistry, physics, and medicine. Daria Fedyukina. Cavagnero Group. February 26, 2009. What is inside?. Brain exploration, circa 6500 BC. What is MRI? History of MRI.

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magnifying from inside where a smart gadolinium unites chemistry physics and medicine

UW-Madison

Chemistry Department

Magnifying from inside: where a smart gadolinium unites chemistry, physics, and medicine

Daria Fedyukina

Cavagnero Group

February 26, 2009

what is inside
What is inside?

Brain exploration, circa 6500 BC

what is mri history of mri
What is MRI? History of MRI

Magnetic resonance imaging (MRI)

is an non-invasive imaging technique

used primarily in medical settings

to produce high quality images of the inside of the human body.

1973 - Paul Lauterbur

first demonstrated MRI

1975 - Richard Ernst

magnetic resonance imaging

using phase and frequency encoding

1977 - Raymond Damadian

MRI of the whole body

2003 - Paul Lauterbur and Peter Mansfield

The Nobel Prize in Physiology

for work on the development of MRI .

Clinical MRI scanner. Siemens AVANTO, 1.5T

Beckmann, N. et al. NMR Biomed. 2007, 20, 154

advantages and disadvantages of mri
Advantages and Disadvantages of MRI

Advantages of MRI:

  • noninvasiveness
  • using non-ionising radiation
  • high spatial resolution
  • soft-tissue discrimination (contrast) in any imaging plane.
  • morphological and functional information

Disadvantages of MRI:

Disadvantages of MRI:

  • Low sensitivity
  • Long scanning time
  • Cost

How do scientists overcome weaknesses of MRI technique?

Willmann, J.K., et al. Nature Reviews, 2008, 7, 591

content of the talk
Content of the talk
  • Physics of MRI
  • Enhancing the contrast of MR image
      • Contrast Agents (CA) in MRI
      • Mechanism of CA action
      • Clinically approved CA
  • 3. Advances in CA for MRI
      • Extracellular CAs examples
        • Ca-sensitive CA
        • Fibrin-sensitive CA
        • Thiol-sensitive CA
      • CA for cell labeling
      • Intracellular CA
physics of mri nmr and mri comparison
Physics of MRI: NMR and MRI comparison
  • MRI is based on the principles of nuclear magnetic resonance.
  • MRI primarily images the NMR signal from the hydrogen nuclei.
  • Hydrogen nuclei are from water and fat.

Fat

H2O

1H NMR

1H NMR spectrum of Lipoma B

MRI

MRI of lipoma B in the brain

Frund, R., et al. Frontiers in Bioscience, 1997, 2, 13

physics of mri frequency encoding
Physics of MRI: Frequency encoding
  • MR signal itself does not possess any directional information
  • Magnetic field gradient is applied
  • The object in a magnetic field
  • Magnetic field gradient in +x direction
  • 1D 1H NMR spectrum is recorded

Hornak, J.P. The Basics of MRI, online book, 2007

Mitchell, D.G. MRI Principles, Saunders Company press, 1999

physics of mri phase encoding
Physics of MRI: Phase encoding
  • A second spectrum is recorded with the gradient
  • at a 1o angle to the +x axis
  • The process is repeated over the 360 angles
  • The data are backprojected through space
  • to obtain an image

Hornak, J.P. The Basics of MRI, online book, 2007

Mitchell, D.G. MRI Principles, Saunders Company press, 1999

physics of mri t 1 weighted image
Physics of MRI: T1-weighted image
  • T1 relaxation
    • Efficiency of energy transfer from a spin to surroundings.
    • Property of a tissue.

H2O – moves fast → long T1 relaxation times (~seconds)

Fat – moves slower → short T1, relaxation times (~milliseconds)

  • T1-weighted image is based on the differences
  • in T1 relaxation times among tissues
  • Fat appears brighter than water
  • To increase intensity – decrease T1
  • To improve the contrast – increase ΔT1

Brain with lipoma B

Fat

Frund, R., et al. Frontiers in Bioscience, 1997, 2, 13

Mitchell, D.G. MRI Principles, Saunders Company press, 1999

H2O

content of the talk10
Content of the talk
  • Physics of MRI
  • Enhancing the contrast of MR image
      • Contrast Agents (CA) in MRI
      • Mechanism of CA action
      • Clinically approved CA
  • 3. Advances in CA for MRI
      • Extracellular CAs examples
        • Ca-sensitive CA
        • Fibrin-sensitive CA
        • Thiol-sensitive CA
      • CA for cell labeling
      • Intracellular CA
contrast agents introduction
Contrast Agents: Introduction
  • Contrast Agents (CA)
    • paramagnetic or ferromagnetic substances
    • reduce relaxation times for water protons close to CAs

Low density

tissue of unknown

morphology

Before CA injection

After CA injection

  • The overwhelming majority of CAs contain:
    • Gd(III)
    • Eight-dentate ligands like DTPA and DOTA

Merbach, A.E. (ed.), The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging,

John Wiley and Sons, 2001

contrast agents in mri gadolinium iii
Contrast Agents in MRI: Gadolinium(III)

Advantages of using Gd(III) in CA:

  • High electron spin quantum S = 7/2

Gd3+ [Xe]4f7

Gdeffeciently relaxes nearby protons

  • Low energy barrier between 8- and 9-coordinate states

Fast exchange of relaxed water with the bulk water

Disadvantages of using Gd(III) in CA:

  • High toxicity of free Gd3+ (LD50 ≈ 5 mg/kg)

Caravan, P., Chem. Soc. Rev., 2006, 35, 512

Werner, E.J, et al., Angew. Chem. Int. Ed., 2008, 47, 8568

contrast agents dtpa and dota
Contrast Agents: DTPA and DOTA

DTPA

DOTA

Diethylenetriaminepentaacetic acid

N,N’,N”,N”’-tetrakis(carboxymethyl)-

1,4,7,10-tetraazacyclododecane

Advantages of using DTPA/DOTA in CA:

  • Thermodynamically and kinetically stable complexes with Gd(III)
  • Highly hydrophilic → do not enter cells
  • Eight-dentate → 9th site is open for H2O
  • No intercalation groups → do not integrate into DNA
  • Relatively easy to synthesize → production in large scale

Disadvantages of using DTPA/DOTA in CA:

  • CAs are not able to target disease states
  • Short circulation time (life time ~ 15 min)

Roat-Malone, R.M., Bioinorganic Chemistry, Wiley-Interscience, 2002

Werner, E.J, et al., Angew. Chem. Int. Ed., 2008, 47, 8568

mechanism of ca action relaxivity
Mechanism of CA action: Relaxivity

Good Contrast Agent:

  • Paramagnetic ion must efficiently relax the water
  • Relaxed water must exchange rapidly with the bulk water

Relaxivity:

Commercial agents relaxivity: r1≈ 4 mM-1s-1

Requirement for robust clinical exam: ΔR1 ≥ 0.5 s-1

→ [CA] ≥ 125 µM

Goal – increase relaxivity of a CA

Caravan, P., Chem. Soc. Rev., 2006, 35, 512

Bloembergen, N., Morgan, L.O., J. Chem. Phys., 1961, 34, 842

mechanism of ca action what affects relaxivity
Mechanism of CA action: What affects relaxivity?

1. Hydration number, q

  • High q:
    • favors relaxivity
    • destabilizes Gd(III) complex

2. Water exchange time, τm

Decrease τm

3. Relaxation time of the bound water, T1m

Usually T1m > τm.

Often T1m limits the relaxivity.

Decrease T1m

Caravan, P., Chem. Soc. Rev., 2006, 35, 512

Bloembergen, N., Morgan, L.O., J. Chem. Phys., 1961, 34, 842

mechanism of ca action what affects t 1m
Mechanism of CA action: What affects T1m?

Correlation time:

Rotational

diffusion

Electronic

relaxation

Water

exchange

Rotational diffusion dominates → Optimize τR

For clinically used magnetic fields increase τR

Use bulky ligands with isotropic rotation

Bloembergen, N., Morgan, L.O., J. Chem. Phys., 1961, 34, 842

Bloembergen, N., J. Chem. Phys., 1957, 27, 572 Caravan, P., et al., Chem. Rev., 1999, 99, 2293

mechanism of ca action summary
Mechanism of CA action: summary
  • Factors leading to the increase in relaxivity:
    • Hydration number
    • low q – low relaxivity,
    • high q – high relaxivity BUT low stability
    • Water exchange time
    • low τm – high relaxivity
    • Rotational diffusion time
    • low τR – low relaxivity
    • optimized τR – high relaxivity
    • very high τR – low relaxivity
clinically approved ca dtpa based
Clinically approved CA: DTPA-based

[Gd(DTPA)(H2O)]2- (NMG)22+

Magnevist: BSP, 1988

Blood vessel agent

r1 = 3.8(0.5T)

[Gd(DTPA-bmea)(H2O)]

OptiMARK: Mallinckrodt

Brain, spine, and liver agent

r1 = 4.7 (0.5T)

Uggeri, F., et al., Inorg. Chem., 1995, 34, 633

clinically approved ca dota based
Clinically approved CA: DOTA-based

[Gd(DOTA)(H2O)]- (NMG)+

Dotarem: Guerbet

Central nervous system

Whole body imaging

r1 = 3.6 (0.5T)

[Gd(DO3A-butrol)(H2O)]

Gadovist: BSP

Central nervous system

Can be taken in high doses

r1 = 3.6 (0.5T)

Weisman, G.R., Reed, D.P., J. Org. Chem., 1996, 61, 5186

synthesis of dtpa and its derivatives
Synthesis of DTPA and its derivatives

diethylenetriamine

US Patent 4,859,451

US Patent 5,137,711

Frost, A.E. Nature, 1956, 178, 322

synthesis dota and its derivative
Synthesis DOTA and its derivative

Stetter, H. and Frank, W., Angew. Chem. Int. Ed. Engl., 1976, 15, 686

Gries, H. Topics in Current Chemistry, 2002, 221, pp. 1-24

content of the talk22
Content of the talk
  • Physics of MRI
  • Enhancing the contrast of MR image
      • Contrast Agents (CA) in MRI
      • Mechanism of CA action
      • Clinically approved CA
  • 3. Advances in CA for MRI
      • Extracellular CAs examples
        • Ca-sensitive CA
        • Fibrin-sensitive CA
        • Thiol-sensitive CA
      • CA for cell labeling
      • Intracellular CA
extracellular cas ca 2 sensitive
Extracellular CAs: Ca2+ -sensitive

Monitoring calcium dynamics in the brain

Gd-DOPTRA

  • Sensitive to [Ca2+] and [Zn2+]
  • Insensitive to [Mg2+]
  • Higher q upon chelation
  • Bulky ligand with lowered
  • rotational diffusion rate
  • Relatively easy synthesis

Free(-Ca2+)

bound(+Ca2+)

Dhingra, K., et al., Chem. Commun., 2008, 3444

extracellular cas ca 2 sensitive24
Extracellular CAs: Ca2+ -sensitive

Major, J.L., et al. , PNAS,2007, 104, 13881

extracellular cas fibrin sensitive
Extracellular CAs: Fibrin-sensitive

Thrombus Imaging

Thrombus – a blood clot with [Fibrin] ≈ 10-100 µM

Fibrin-binding Gd-DTPA-based CAs:

  • GdDTPA-GLPCDYYGTCLD (CA1)
  • (GdDTPA)4-(LPCDYYGTCBip·d)2 (CA2)

d – D-Asp

Bip – Biphenylalanine

Nair, S.A., et al., Angew. Chem. Int. Ed., 2008, 47, 4918

extracellular cas fibrin sensitive26
Extracellular CAs: Fibrin-sensitive

Fibrin-binding Gd-DTPA-based CAs:

GdDTPA-GLPCDYYGTCLD (CA1)

(GdDTPA)4-(LPCDYYGTCBip·d)2 (CA2)

CA1

CA2

K1

K2

Nair, S.A., et al., Angew. Chem. Int. Ed. 2008, 47, 4918

extracellular cas fibrin sensitive27
Extracellular CAs: Fibrin-sensitive

triethylenetetraamine derivative

(GdDTPA)4-(L·P·C·D·Y·Y·G·T·C·Bip·d)2

Nair, S.A., et al., Angew. Chem. Int. Ed., 2008, 47, 4918

Overoye-Chan, K., et al., J. Am. Chem. Soc., 2008, 130, 6025

extracellular cas thiol sensitive
Extracellular CAs: Thiol-sensitive

+

Digilio, G., et al., Chem. Commun., 2009, 893

Carrera, C., et al., Dalton Trans., 2007, 4980

contrast agent for cell labeling
Contrast Agent for cell labeling

Targeting exofacial protein thiols

A – Buffer solution

B – GdDO3A 2mM

C – Cellular Pellet

D – GdDO3AS-Act 1mM

E – GdDO3AS-Act 2mM

Gd-DO3AS-Act :

  • 3-fold relaxation enhancement upon binding
  • BUT
  • Partial internalization

Digilio, G., et al., Chem. Commun., 2009, 893

intracellular ca macrophage imaging
Intracellular CA: Macrophage imaging

Fluorescein

Apolipoprotein E derived lipopeptide

Vucic, E., et al., J. Am. Chem. Soc., 2009, 131, 406

intracellular ca macrophage imaging31
Intracellular CA: Macrophage imaging

CM

MRI

A

P2fA2

Micelle forming

Lipid

Gd-DTPA-DSA

Bilayer forming

Lipid

B

High P2fA2

content

High content

of Gd-DTPA-DSA

C

  • Highest relaxivity and uptake were found
  • for particles with 33% P2fA2
  • At lower percent of P2fA2
  • rotational diffusion is limiting
  • At higher percent of P2fA2
  • water exchange is limiting

A – untreated cells

B – treated with 50% P2fA2

C – treated with 33% P2fA2

Vucic, E., et al., J. Am. Chem. Soc., 2009, 131, 406

summary
Summary
  • MRI is a state-of-the-art technique
    • excellent spatial resolution
    • poor sensitivity
  • Contrast Agents improve sensitivity of MRI
  • Majority of clinically used contrast agents are
  • Gd(III)- and DTPA/DOTA-based
  • Good Contrast Agents
    • increase relaxivity
    • target specific disease states
  • Significant progress in the field of targeted MRI
    • extracellular CA
    • intracellular CA
acknowledgements
Acknowledgements

Practice Talk Attendees:

Tianning Diao

Chris Brown

Chris Shaffer

Jamie Ellis

Kevin Williamson

Olga Dykhno

Shu Yao

Prof. Silvia Cavagnero

Cavagnero Group

Ashok Sekhar

Juana Du

Sarah Weinreis

Pavan Srinath

Peter Culviner

JayashreeNagesh

James Gerken

Thank you for attention!