MRI Contrast Agents

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MRI Contrast Agents

• Jerry Allison Ph.D.
• Chris Wright B.S.
• Tom Lavin B.S.
• Nathan Yanasak Ph.D.
• Tom Hu Ph.D. MBA
• December 12th, 2007

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Outline

• Introduction to MR Contrast Agents
• Exogenous
• Paramagnetic Agents
• Superparamagnetic Agents
• Ferromagnetic Agents
• Positive Contrast Agents
• Negative Contrast Agents
• Route of Administration
• Clinical Based MRI Contrast Agents/Examples

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Outline

• Introduction to MR Contrast Agents
• Exogenous
• Paramagnetic Agents
• Superparamagnetic Agents
• Ferromagnetic Agents
• Positive Contrast Agents
• Negative Contrast Agents
• Route of Administration
• Clinical Based MRI Contrast Agents/Examples

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Contrast Agents

• Exogenous
• Paramagnetic Agents
• Superparamagnetic Agents
• Ferromagnetic Agents
• Positive Contrast Agents
• Negative Contrast Agents
• Route of Administration

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Contrast Agents

• Contrast agents are useful for detection of
  tumors, infection, inflammation, infarction and
  lesions. Contrast agents alter T1, T2, or T2
  of various tissues, producing contrast.
• Barium and iodine compounds are used to enhance
  contrast in x-ray procedures. These compounds
  are sometimes referred to as contrast media
  since their presence appears directly in the
  images.
• MRI contrast is enhanced using contrast agents
  since the contrast is not directly imaged but
  rather the effect that the magnetic properties of
  the contrast agent has on the relaxation of
  tissues is imaged.

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Contrast Agents (Exogenous)

• A variety of paramagnetic, superparamagnetic and
  ferromagnetic contrast agents can be administered
  i.v., orally or rectally to manipulate tissue
  contrast.
• Contrast agents are generally described by their
  magnetic properties or contrast enhancement.
• paramagnetic agents
• ferromagnetic agents
• superparamagnetic agents

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Contrast Agents (Exogenous)

• Paramagnetic substances have positive magnetic
  susceptibility due to the presence of one or more
  unpaired electrons
• Gd3 7 unpaired electrons
• Dy3 5 unpaired electrons
• Fe2 5 unpaired electrons
• Mn3 4 unpaired electrons

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Contrast Agents (Exogenous)

• Ferromagnetic substances are solids with
  crystalline structures that develop small
  magnetic domains. When placed in an external
  magnetic field (B0), the multitude of magnetic
  domains will align with the field and retain that
  magnetism when removed from the Bo field.
• Iron, Nickel and Cobalt have ferromagnetic
  properties.

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Contrast Agents (Exogenous)

• Superparamagnetic substances are smaller solid
  particles each of which develop a single
  domain. Like ferromagnetic substances, the
  domains align in the external magnetic field
  unlike ferromagnetic particles, the alignment
  disperses when the paramagnetic substance is
  removed from the external field.
• Magnetite Fe3O4 (i.v. or oral)

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Contrast Agents

• Positive contrast agents
• Positive contrast agents cause hyperintensity on
  T1 weighted images. The presence of a positive
  agent stimulates an increase in spin flip
  transitions resulting in reduced T1 values and
  increased brightness on T1 weighted images.

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Contrast Agents T1 Relaxation Time
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Contrast Agents (Positive Contrast Agents)
Lets examine the most common positive contrast
agent Gd - DTPA Gadolinium (Gd) is atomic
number 64 and hence, has 64 electrons. The
electrons are distributed in shells as follows k
l m n
o p 1 2 3
4 5 6 s s
p s p d s p d f s p d
s 2 2 6 2 6 10 2 6 10 7
2 6 1 2
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Periodic Table
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Contrast Agents

• Positive contrast agents
• There are seven different orbits in the 4f
  electron subshell, each of which can hold up to
  two electrons (spin up spin down or
  clockwise counterclockwise).
• In Gd, the seven electrons of the 4f subshell
  each occupy a different orbit resulting in 7
  unpaired electrons in the atom. Each of the
  unpaired electrons has an electron magnetic
  moment 658 times larger than the nuclear magnetic
  moment of the hydrogen proton.

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Contrast Agents

• Positive contrast agents
• Gd is a toxic metal that binds to membranes,
  transport proteins, enzymes, lung, liver, spleen
  and bone. Small amounts of metallic Gd can cause
  liver necrosis. Gd is complexed in a chelate and
  is rapidly cleared from the body via glomerular
  filtration.

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Contrast Agents

• Positive contrast agents
• 80 excretion by kidneys in 3 hours
• 98 in excreta in 1 week
• In Gd-DTPA, the toxic metal ion is complexed in a
  chelate (lobster claw). The chelate is the
  N-methylglucamine salt of diethylenetriamine
  pentaacetic acid. Chelation determines the
  effect that the paramagnetic substance will have
  on proton relaxation. The access of water
  molecules to the Gd ion is determined by the
  structure and size of the chelation agent.

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Contrast Agents

• Positive contrast agents
• The metal chelate complexes affect the net
  magnetic moment of the contrast agent molecule.
  Toxicity, solubility, biodistribution, plasma
  residence time, elimination routes and relaxivity
  properties of Gd chelates are modified by the
  details of the chelating agent.

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What is Nephrogenic Fibrosing Dermopathy (NFD)?

• Also known as Nephrogenic Systemic Fibrosis
  (NSF)
• a condition that, so far, has occurred only in
  people with kidney disease. There is no
  convincing evidence that NSF is caused by a
  medication, a microorganism, or by dialysis.
  There have been no cases identified prior to
  early 1997. At this point it appears NSF is a
  systemic disorder with its most prominent and
  visible effects in the skin. For this reason,
  Nephrogenic Systemic Fibrosis has been suggested
  as an equivalent terminology in those previously
  diagnosed with NFD, and is preferred in that it
  more accurately reflects our current
  understanding of the disorder.

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What is Nephrogenic Fibrosing Dermopathy (NFD)?

• Neither the duration of kidney disease nor its
  underlying cause are related to the development
  of NSF. Some patients with NSF develop skin
  tightening in the earliest stages of kidney
  disease, and others may have had kidney disease
  for years. Specific triggers for the development
  of NSF are still being investigated. Recent
  reports have strongly correlated the development
  of NSF with exposure to gadolinium-containing MRI
  contrast agents. Further information from the US
  Food and Drug Administration regarding this
  observation can be found here (http//www.fda.gov
  /cder/drug/advisory/gadolinium_agents.htm).

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Nephrogenic systemic fibrosis a serious late
adverse reaction to gadodiamide, H. S. Thomsen,
Eur Radiol 16 26192621 (2006)

• It is striking that many radiologists were
  unaware that nephrogenic systemic fibrosis may be
  a serious late adverse reaction to
  gadolinium-based contrast media despite the fact
  that the Food and Drug Administration issued a
  warning 8 June 2006.
• More than 150 patients have developed NSF after
  exposure to a Gd-based contrast medium. The
  overwhelming majority (90) had had gadodiamide
  with certainty. Regarding the remaining patients
  it is still unknown what they had.
• NSF after exposure to gadodiamide has been seen
  in Caucasian and Afro-Americans. It has been
  observed also in the United Kingdom, USA, the
  Netherlands, France, Belgium, Austria and
  Denmark. The patients were either on dialysis or
  had reduced renal function (highest GFR reported
  20 ml/min.).
• There are no reports of NSF in patients with
  normal kidney function. Around 200 million
  patients have had injections of a
  gadolinium-based contrast agent since the early
  1980s. A population of more than 30 million
  patients has received gadodiamide. So, in
  patients without ESRD, all gadolinium-based
  contrast agents seem to be safe.
• Exposure to a gadolinium-based contrast agent
  cannot be documented in all patients developing
  NSF.

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Nephrogenic systemic fibrosis a serious late
adverse reaction to gadodiamide, H. S. Thomsen,
Eur Radiol 16 26192621 (2006)

• It is striking that many radiologists were
  unaware that nephrogenic systemic fibrosis may be
  a serious late adverse reaction to
  gadolinium-based contrast media despite the fact
  that the Food and Drug Administration issued a
  warning 8 June 2006.
• More than 150 patients have developed NSF after
  exposure to a Gd-based contrast medium. The
  overwhelming majority (90) had had gadodiamide
  with certainty. Regarding the remaining patients
  it is still unknown what they had.
• NSF after exposure to gadodiamide has been seen
  in Caucasian and Afro-Americans. It has been
  observed also in the United Kingdom, USA, the
  Netherlands, France, Belgium, Austria and
  Denmark. The patients were either on dialysis or
  had reduced renal function (highest GFR reported
  20 ml/min.).
• There are no reports of NSF in patients with
  normal kidney function. Around 200 million
  patients have had injections of a
  gadolinium-based contrast agent since the early
  1980s. A population of more than 30 million
  patients has received gadodiamide. So, in
  patients without ESRD, all gadolinium-based
  contrast agents seem to be safe.
• Exposure to a gadolinium-based contrast agent
  cannot be documented in all patients developing
  NSF.

25
Nephrogenic systemic fibrosis a serious late
adverse reaction to gadodiamide, H. S. Thomsen,
Eur Radiol 16 26192621 (2006)

• It is striking that many radiologists were
  unaware that nephrogenic systemic fibrosis may be
  a serious late adverse reaction to
  gadolinium-based contrast media despite the fact
  that the Food and Drug Administration issued a
  warning 8 June 2006.
• More than 150 patients have developed NSF after
  exposure to a Gd-based contrast medium. The
  overwhelming majority (90) had had gadodiamide
  with certainty. Regarding the remaining patients
  it is still unknown what they had.
• NSF after exposure to gadodiamide has been seen
  in Caucasian and Afro-Americans. It has been
  observed also in the United Kingdom, USA, the
  Netherlands, France, Belgium, Austria and
  Denmark. The patients were either on dialysis or
  had reduced renal function (highest GFR reported
  20 ml/min.).
• There are no reports of NSF in patients with
  normal kidney function. Around 200 million
  patients have had injections of a
  gadolinium-based contrast agent since the early
  1980s. A population of more than 30 million
  patients has received gadodiamide. So, in
  patients without ESRD, all gadolinium-based
  contrast agents seem to be safe.
• Exposure to a gadolinium-based contrast agent
  cannot be documented in all patients developing
  NSF.

26
Nephrogenic systemic fibrosis a serious late
adverse reaction to gadodiamide, H. S. Thomsen,
Eur Radiol 16 26192621 (2006)

• It is striking that many radiologists were
  unaware that nephrogenic systemic fibrosis may be
  a serious late adverse reaction to
  gadolinium-based contrast media despite the fact
  that the Food and Drug Administration issued a
  warning 8 June 2006.
• More than 150 patients have developed NSF after
  exposure to a Gd-based contrast medium. The
  overwhelming majority (90) had had gadodiamide
  with certainty. Regarding the remaining patients
  it is still unknown what they had.
• NSF after exposure to gadodiamide has been seen
  in Caucasian and Afro-Americans. It has been
  observed also in the United Kingdom, USA, the
  Netherlands, France, Belgium, Austria and
  Denmark. The patients were either on dialysis or
  had reduced renal function (highest GFR reported
  20 ml/min.).
• There are no reports of NSF in patients with
  normal kidney function. Around 200 million
  patients have had injections of a
  gadolinium-based contrast agent since the early
  1980s. A population of more than 30 million
  patients has received gadodiamide. So, in
  patients without ESRD, all gadolinium-based
  contrast agents seem to be safe.
• Exposure to a gadolinium-based contrast agent
  cannot be documented in all patients developing
  NSF.

27
Nephrogenic systemic fibrosis a serious late
adverse reaction to gadodiamide, H. S. Thomsen,
Eur Radiol 16 26192621 (2006)

• It is striking that many radiologists were
  unaware that nephrogenic systemic fibrosis may be
  a serious late adverse reaction to
  gadolinium-based contrast media despite the fact
  that the Food and Drug Administration issued a
  warning 8 June 2006.
• More than 150 patients have developed NSF after
  exposure to a Gd-based contrast medium. The
  overwhelming majority (90) had had gadodiamide
  with certainty. Regarding the remaining patients
  it is still unknown what they had.
• NSF after exposure to gadodiamide has been seen
  in Caucasian and Afro-Americans. It has been
  observed also in the United Kingdom, USA, the
  Netherlands, France, Belgium, Austria and
  Denmark. The patients were either on dialysis or
  had reduced renal function (highest GFR reported
  20 ml/min.).
• There are no reports of NSF in patients with
  normal kidney function. Around 200 million
  patients have had injections of a
  gadolinium-based contrast agent since the early
  1980s. A population of more than 30 million
  patients has received gadodiamide. So, in
  patients without ESRD, all gadolinium-based
  contrast agents seem to be safe.
• Exposure to a gadolinium-based contrast agent
  cannot be documented in all patients developing
  NSF.

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More Information on Nephrogenic Fibrosing
Dermopathy (NFD)

• International Society for Magnetic Resonance in
  Medicine (ISMRM www.ismrm.org)
• Gadobenate Dimeglumine (marketed as MultiHance)
• Gadodiamide (marketed as Omniscan)
• Gadopentetate Dimeglumine (marketed as
  Magnevist)
• Gadoteridol (marketed as ProHance)
• Gadoversetamide (marketed as OptiMARK)

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More Information on Nephrogenic Fibrosing
Dermopathy (NFD)

• http//cds.ismrm.org/protected/NSF/

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Contrast Agents

• Positive contrast agents
• When injected i.v., if Gd-DTPA were to mix with
  an equal volume of blood, a concentration of 250
  mmol / liter would result. The concentration
  of Gd-DTPA immediately after injection will be
  200 times higher that the eventual diluted
  concentration in the blood pool. When the bolus
  injection first undergoes mixing in the left
  ventricle, the concentration would be 47 mmol /
  liter.

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Contrast Agents

• Positive contrast agents
• This concentration would be rapidly diluted to
  1.3 mmol / liter by the blood pool (after the
  initial high concentration first pass). The
  kidney will subsequently have a relatively high
  concentration of Gd-DTPA as glomerular filtration
  acts to remove Gd-DTPA from plasma (up to 1-2
  mmol / liter).

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Contrast Agents

• Positive contrast agents
• The introduction of a paramagnetic contrast agent
  into the blood pool will affect the MRI
  relaxation properties of perfused tissues. The
  paramagnetic contrast agent will affect tissue
  relaxation through dipole-dipole interactions
  (T2), molecular motion (T1), and magnetic
  susceptibility (T2).

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Contrast Agents

• Positive contrast agents
• Dipole-dipole interactions are determined by
• Strength of the magnetic moments involved
• The Gd-DTPA molecule has a strong magnetic
  moment compared to an ordinary proton, resulting
  in strong dipole-dipole interactions with tissue
  protons.
• Distance between magnetic moments
• The structure of the chelating agent will
  determine the distance between the unpaired
  electrons of the Gd ion and water protons.

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Contrast Agents

• Positive contrast agents
• Dipole-dipole interactions are determined by
• Motion
• The Gd-DTPA molecule tumbles at a frequency that
  is more conducive to stimulation of spin flip
  transitions than is the much higher tumbling
  frequency of water molecules.
• It is possible to adjust the tumbling frequency
  of a contrast agent by binding the agent to
  larger molecules. Enhanced Gd-DTPA relaxivity
  has been accomplished by binding Gd-DTPA to serum
  albumin.

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Contrast Agents

• Positive contrast agents
• Dipole-dipole interactions are determined by
• Magnetic susceptibility
• paramagnetic contrast agents have high magnetic
  susceptibility, resulting in dephasing caused by
  increases/decreases in the Larmor frequency due
  to local increases/decreases in B0.

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Contrast Agents

• Negative contrast agents
• Negative contrast agents cause hypointensity on
  T2 weighted images. Negative agents produce
  substantial magnetic inhomogeneity due to
  magnetic susceptibility. Magnetic inhomogeneity
  perturbs the Larmor frequency of protons,
  resulting in a loss of phase coherence and
  reduced T2 values.

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Contrast Agents

• Negative contrast agents
• While positive agents are called relaxation
  agents, negative agents are called shift agents,
  chemical shift agents or frequency agents.
• Examples of negative agents are Dysprosium
  chelates and superparamagnetic particles.
  Positive agents reduce both T1 and T2, but are
  principally used to enhance T1 weighting.

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Contrast Agents T2 Relaxation Time
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Contrast Agents

• Negative contrast agents
• Superparamagnetic agents cause large
  perturbations in the local magnetic field,
  resulting in dramatic reductions in T2 or T2 .
  Since these solid particles do not tumble at the
  Larmor frequency, T1 relaxation is relatively
  unaffected.
• Ultrasmall superparamagnetic iron oxides can also
  reduce T1 and produce T1 weighting.

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Contrast Agents

• Negative contrast agents
• Dysprosium (Dy) chelates are paramagnetic but act
  to reduce T2 or T2 without affecting T1 .
• The electron spin relaxation of the unpaired
  electrons in Dysprosium is very short. The
  magnetic moments of the electrons change
  orientations too rapidly to efficiently stimulate
  T1 relaxation.

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Outline

• Introduction to MR Contrast Agents
• Exogenous
• Paramagnetic Agents
• Superparamagnetic Agents
• Ferromagnetic Agents
• Positive Contrast Agents
• Negative Contrast Agents
• Route of Administration
• Clinical Based MRI Contrast Agents/Examples

43
Gd-based MR Contrast Agents

• Gadobenate Dimeglumine (marketed as MultiHance)
• Gadodiamide (marketed as Omniscan)
• Gadopentetate Dimeglumine (marketed as Magnevist)
  
• Gadoteridol (marketed as ProHance)
• Gadoversetamide (marketed as OptiMARK)

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Gd-based MR Contrast Agents

• MultiHance by Bracco Diagnostics
• Gd-BOPTA gadobenate dimeglumine
• dose 0.05 mmol/kg for Liver MRI 0.1 mmol/kg
  for CNS

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Gd-based MR Contrast Agents

• Omniscan by Nycomed (Winthrop)
• Gd-DTPA-BMA gadodiamide
• Approved for double dose in adults
• Dose 0.1 mmol/kg (0.2 ml/kg)
• followed by 0.2 mmol/kg (0.4 ml/kg) if necessary
• Since non-ionic, can bolus inject
• Approved for pediatrics (0.1 mmol/kg )

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Gd-based MR Contrast Agents

• Magnevist by Berlex
• Gd-DTPA gadopentate dimeglumine
• dose 0.1 mmol/kg (0.2 ml/kg)
• approved for pediatrics 0.1 mmol/kg
• ionic, high osmolality

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Gd-based MR Contrast Agents

• ProHance by Bracco (Squibb)
• Gd-HP-DO3A gadoteridol
• Approved for double dose in adults
• Dose 0.1 mmol/kg (0.2 ml/kg)
• followed by 0.2 mmol/kg (0.4 ml/kg) if necessary
• Less toxic (vomiting at MCG)
• Since non-ionic, can bolus inject
• More stable (less Gd release)
• Approved for pediatrics (0.1 mmol/kg )

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Gd-based MR Contrast Agents

• OptiMARK by Mallinckrodt Inc.
• Gd-DTPA-BMEA gadoversetamide
• dose 0.1 mmol/kg / 0.2 mL/kg

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Indications and Usage

• Central Nervous System
• Extracranial/Extraspinal Tissue
• Body

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Relative Concentration for Indications

• The concentration of MRI contrast is intermediate
  to x-ray and nuclear medicine contrast.
• 10-3 to 10-2 mmol/kg X-ray (iodine)
• 10-5 to 10-3 mmol/kg MRI
• lt 10-7 mmol/kg Nuclear Medicine

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Mn-based MR Contrast Agents

• Manganese dipyridoxyl-diphosphate (MnDPDP
  Teslascan)

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Fe-Based MR Contrast
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