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Medical Imaging in Clinical Trials pp 327–357Cite as

Contrast Agents in Radiology

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Abstract

To noninvasively diagnose disease and to describe response to therapy regarding morphology (e.g., size, structure) and (patho)physiology (e.g., blood perfusion) as well as cell function optimal image contrast is key. In our various body compartments in vivo contrast can be altered and improved by changing its intensity and distribution over time. This imaging fortune has been established by various contrast agents typically administered intravenously. Imaging methods in the field of ultrasound, magnetic resonance imaging, as well as computed tomography are continuously being improved by safe, valid, and efficient contrast agents. New targeted and specific agents are in the pipeline, but there are still a few more steps to go to reach market approval.

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Authors and Affiliations

  1. Institute for Diagnostic, Interventional, and Pediatric Radiology (DIPR), Inselspital—University Hospital Bern, Freiburgstr. 10, Bern, 3010, Switzerland

    Hendrik von Tengg-Kobligk MD, Dr. med., Priv-Doz

  2. Department of Diagnostic and Interventional Radiology (DIR), University Hospitals Heidelberg, Heidelberg, 69120, Germany

    Hendrik von Tengg-Kobligk MD, Dr. med., Priv-Doz

  3. Department of Radiology, German Cancer Research Center (DKFZ), INF 280, Heidelberg, 69120, Germany

    Hendrik von Tengg-Kobligk MD, Dr. med., Priv-Doz

  4. Department of Engineering Science, Institute of Biomedical Engineering, Old Road Campus Research Building, University of Oxford, Hedington, Oxfordshire, OX3 7DQ, UK

    Amit Mehndiratta MBBS, DPhil (Oxon)

  5. Department of Nuclear Medicine, University Hospitals Heidelberg, INF 400, Heidelberg, 69120, Germany

    Frederik L. Giesel MD, MBA

Authors
  1. Hendrik von Tengg-Kobligk MD, Dr. med., Priv-Doz
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  2. Amit Mehndiratta MBBS, DPhil (Oxon)
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  3. Frederik L. Giesel MD, MBA
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Corresponding author

Correspondence to Hendrik von Tengg-Kobligk MD, Dr. med., Priv-Doz .

Editor information

Editors and Affiliations

  1. Medical Affairs, BioClinica Inc., Newtown, Pennsylvania, USA

    Colin G. Miller

  2. Department of Strategy and Regulatory Affairs, TherapeuticsMD, Boca Raton, Florida, USA

    Joel Krasnow

  3. Dept. of Radiology, Columbia University Medical Center, New York, New York, USA

    Lawrence H. Schwartz

Appendices

Appendix 15.1: Overview of Available Nonionic, Low-osmolar, and Iso-osmolar Contrast Media and Their Physicochemical Properties

Generic name (mg I/mL)

Trade name(s)

Manufacturer

Labeled indicationsa

Type, ionicity

Osmolality (mOsm/kg H2O)b, c

Viscosity at 37 °C (mPa × s)

Molecular weight (Da)

Iohexol (300/350)

Omnipaque

GE Healthcare

Myelography, cisternography, ventriculography (intrathecally), head, body, GI tract

LOCM nonionic (monomer)

672/844

6.3/10.4

821

Omnitrast

Bayer HealthCare Juste

Omnigraf

Iopentol (300)

Imagopaque

GE Healthcare

Whole body, angiography, GI tract

LOCM nonionic (monomer)

640/818

6.5/12.0

835

Iopamidol (300/370)

Isovue

Bracco

Head, whole body

LOCM nonionic (monomer)

616/796

4.7/9.4

777

Iopamiron

Iopamiron

Niopam

Solutrast

Iopromide (300/370)

Ultravist

Bayer HealthCare

Whole body

LOCM nonionic (monomer)

607/774

4.9/10.0

791

CT and angiography

Ioversol (300/350)

Optiray

Covidien

Head, body

LOCM nonionic (monomer)

651/792

5.5/9.0

807

Iobitridol (300/350)

Xenetix

Guerbet

Head, whole body

LOCM nonionic (monomer)

695/915

6.0/10.0

835

Ioxilan (300/350)

Oxilan

Guerbet

Head, body

LOCM nonionic (monomer)

585/695

5.1/8.1

791

Iomeprol (300/400)

Imeron

Bracco

Brain, body, cavernosography, myelography, urography

LOCM nonionic (monomer)

521/726

4.5/12.6

777

Iodixanol (320)

Visipaque

GE Healthcare

Head, body

IOCM nonionic (dimer)

290

11.8

1,550

  1. IOCM iso-osmolar contrast media, LOCM low-osmolar contrast media
  2. aLabeled indications may vary in different in countries/continents. Some CM are not even available in certain countries
  3. bOsmolality values differ with measuring technique
  4. cValues can be measured in a pure solution of the active substance in water or in the commercial product

Appendix 15.2: Physicochemical Properties of Tissue-specific and Nonspecific MR Contrast Agents

Lab name

Ionicity

Chemical structure

log K

log K′

Osmolality osmol/kg H2O (37 °C)

Viscosity (mPa s) (37 °C)

WS r1

HP r1

HP r2

HP 3.0T13y r1/r2

[Gd-DTPA]2−

2−

Linear

22.14

17.74

1.962

2.92

3.83q

4.93z

6.33z

3.7/5.2

Gd-BT-DO3A

Neutral

Macrocyclic

21.81

17.11

1.602

5.02

3.62r

5.68z

6.58z

n.a.

Gd-HP-DO3A

Neutral

Macrocyclic

23.84

16.92

0.634

1.44

3.77q

4.67c

5.37c

3.7/5.7

[Gd-BOPTA]2−

2−

Linear

22.63

18.42

1.972

5.32

4.42

9.72z

12.52z

5.2/11.0

[Gd-DOTA]1−

1−

Macrocyclic

25.45

18.25

1.3510

2.010

3.57q

4.37c

5.07c

3.5/4.9

Gd-DTPA-BMA

Neutral

Linear

16.94

14.94

0.654

1.44

3.97r

4.67c

5.17c

4.0/5.6

Gd-DTPA-BMEA

Neutral

Linear

16.86

15.0

1.106

2.06

4.6

3.8c

n.a.

n.a.

Gd-EOB-DTPA

2−

Linear

23.59

18.711

0.8811

1.211

5.511m

8.6

n.a.

6.2/4.0

[Mn-DPDP]2−

2−

Linear

n.a.

n.a.

0.302

0.82

n.a.

2.312

4.012

n.a.

[Gadophostriamine trisodium]3−

3−

Linear

22.411

18.911

0.8311

1.811

6.611

47.213

57.613

9.9/73

SHU555A

Neutral

Coated with carboxydextran

–

–

0.3211

1.0311

23.613

1513

10113

3.3/160

AMI-25

Negat. charged

Coated with dextran

–

–

0.3410

1.310 (20 °C)

20.213

2414

10714

2.7/45

AMI-227

Negat. charged

Coated with dextran

–

–

0.3610

1.310 (25 °C)

2810

23.014

51.014

n.a.

[P792]1−

1−

Macrocyclic

–

–

0.3010

7.210

4210

4810

n.a.

n.a.

Gadomer-17

Neutral

Polyamide

–

–

0.3811

7.011

17.311

18.711

2311

13/25

  1. Relaxivitiesr1 and r2 (mM−1/s) were measured under the following conditions; note indicated exceptions: WS water solution, 0.47 T (20 MHz); pH 7.3; 0.15 M NaCl solution: q39 °C; r40 °C; tdistilled water; HP human plasma, 0.47 T (20 MHz); yplasma, 37 °C, zheparinized, 39 °C; e40 °C; f1.0 T; g1.5 T, kin PBS (37 °C), cin human serum (Seronorm®) at 39 °C; i39 °C, bovine plasma. jRheolab DSR 4000 (Paar Physica, LTD)
  2. logterm: thermodynamic stability for each ion and each chelate; logcond: conditional stability constant for each ion and each chelate: pH 7.4, 25.0 ± 0.1 °C, I = 0.1 M NaClO. (Per: Cacheris WP et al. The relationship between thermodynamics and the toxicity of gadolinium complexes. Magn Reson Imag 1990;8:467–481)
  3. Literature
  4.  1. Staks T, Schuhmann-Giampieri G, Frenzel T, Weinmann HJ, Lange L, Platzek J. Pharmacokinetics, dose proportionality, and tolerability of gadobutrol after single intravenous injection in healthy volunteers. Invest Radiol. 1994;29(7):709–15.
  5.  2. Package Insert, Bayer Healthcare, Germany.
  6.  3. Kirchin MA, Pirovano GP, Spinazzi A. Gadobenate dimeglumine (Gd-BOPTA). An overview. Invest Radiol. 1998;33(11):798–809.
  7.  4. Tweedle MF. The ProHance story: the making of a novel MRI contrast agent. Eur Radiol. 1997;7 Suppl 5:225–30.
  8.  5. Corot C, Idee JM, Hentsch AM, Santus R, Mallet C, Goulas V, Bonnemain B, Meyer D. Structure-activity relationship of macrocyclic and linear gadolinium chelates: investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme. J Magn Reson Imaging. 1998;8(3):695–702.
  9.  6. Rubin DL, Desser TS, Semelka R, Brown J, Nghiem HV, Stevens WR, Bluemke D, Nelson R, Fultz P, Reimer P, Ho V, Kristy RM, Pierro JA. A multicenter, randomized, double-blind study to evaluate the safety, tolerability, and efficacy of OptiMARK (gadoversetamide injection) compared with Magnevist (gadopentetate dimeglumine) in patients with liver pathology: results of a Phase III clinical trial. J Magn Reson Imaging. 1999;9(2):240–50.
  10.  7. de Haën C, Cabrini M, Akhnana L, Ratti D, Calabi L, Gozzini L. Gadobenate dimeglumine 0.5 M Solution for injection (MultiHance(R)): pharmaceutical formulation and physicochemical Properties of a new magnetic resonance imaging contrast medium. J Comput Assist Tomogr. 1999;23(1):S161–S168.
  11.  8. Benner T, Reimer P, Erb G, Schuierer G, Heiland S, Fischer C, Geens V, Sartor K, Forsting M. Cerebral MR perfusion imaging: first clinical application of a 1 M gadolinium chelate (Gadovist 1.0) in a double-blinded randomized dose-finding study. J Magn Reson Imaging. 2000;12(3):371–80.
  12.  9. Speck U. Contrast media: overview, use, and pharmaceutical aspects. 4th ed. Berlin: Springer Science + Business Media; 1994.
  13. 10. Guebert, Corot C. Personal Communication. 2000.
  14. 11. Bayer Healthcare. Personal Communication. 2001.
  15. 12. http://www.mr-tip.com/.
  16. 13. Modo MMJ, Bulte JWM. Molecular and cellular MR imaging. Boca Raton: CRC Press; 2007.
  17. 14. Rubin, GD, Rofsky NM. CT and MR angiography. Philadelphia: Lippincott Williams & Wilkins; 2009.

Appendix 15.3: Overview of Approved and Selected Experimental MR Contrast Media with Approval Status, Distribution, and Physicochemical Properties

Agent name

Lab name

Trade name

Company

Body part (Country)

MW (g/mol)

C (molar)

T ½ in blood (min)

Distribution

Gadopentetate dimeglumine

Gd-DTPA

Magnevist

Bayer HealthCare

CNS, WB (EU, USA, Japan)

938

0.5

~90

Extracellular

Gadobutrol

Gd-BT-DO3A

Gadovist

Bayer HealthCare

CNS (EU, USA)

605

1.0

~90

Extracellular

Gadoteridol

Gd-HP-DO3A

ProHance

Bracco

CNS, WB (EU, USA, Japan)

559

0.5

~90

Extracellular

Gadobenate dimeglumine

Gd-BOPTA

MultiHance

Bracco

CNS, liver (EU, USA)

1058

0.5

~90

Liver/extracellular

Gadoterate meglumine

Gd-DOTA

Dotarem

Guerbet

CNS, WB (EU)

558

0.5

~90

Extracellular

Gadodiamide

Gd-DTPA-BMA

Omniscan

GE Healthcare

CNS, WB (EU, USA, Japan)

574

0.5

~90

Extracellular

Gadoversetamide

Gd-DTPA-BMEA

OptiMARK

Covidien

CNS, liver (EU, USA)

662

0.5

~90

Extracellular

Gadoxetic acid disodium

Gd-EOB-DTPA

Primovist/Eovist

Bayer HealthCare

Liver (EU, USA)

726

0.25

~90

Liver/extracellular

Gadofosveset

Diphenylcyclo-hexyl phospho-diester-Gd-DTPA

ABLAVAR

Lantheus Medical Imaging, Inc.

USA, EU (abd, limbs)

957

0.25

224 ± 30

Intravascular/extracellular

SHU555 A

Ferucarbotran

Resovist/Cliavist

Bayer HealthCare

Discontinued

~700,000

0.5 M Fe/l

144–216/234–348

Liver/RES

AMI-25

Ferumoxides

Feridex IV/Endorem

Berlex/Guerbet

Liver (Japan, EU, USA)

n.a.

0.2 M Fe/l

144

Liver/RES

AMI-227

Ferumoxtran-10

Combidex/Sinerem

Cytogen/Guerbet

Discontinued

n.a.

0.36 M Fe/l

>1,000

LN, RES

Dendrimer

Gadomer-17

n.a.

Bayer HealthCare

Phase II

17,453

0.05

120–180

Intravascular

P792

Gadomeritol

Vistarem

Guerbet

Phase II

6,473

0.035

~120

Intravascular

  1. CNS central nervous system, EU European Union, USA United States of America, LN lymph nodes, RES reticuloendothelial system

Appendix 15.4: Overview of Available US Contrast Media with Current Approval and Distribution Status

Trade name(s)

Manufacturer

Labeled indicationsa

Shell composition

Gas

Availability

Albunex

Covidien

Cardiac

Albumin

Air

Discontinued since availability of Optison

Optison

GE Healthcare

Cardiac

Albumin

Perfluoropropane

US, EU

Echovist

Bayer HealthCare

Hysterosalpinx, cardiac

D-Galactose

Air

Discontinued since availability of Levovist

Levovist

Bayer HealthCare

Cardiovascular, focal liver lesions

Galactose/palmitic acid

Air

EU, Canada, Japan, Chinaa

Imagent

Targeson, Inc

Echocardiography

Surfactant

Perfluorohexane

China

Definity/Luminity

Lantheus Medical Imaging

Cardiac; liver, kidney

Liposome

Octafluoropropane

EMEA= EU

Definity = b

SonoVue

Bracco

CEUS

Surfactant/Phospholipid

Sulfur hexafluoride

EU

Sonazoid

Daiichi Sankyo

Liver, spleen, myocardial perfusion

Lipid stabilized

Perfluorocarbon

Japan

Br14

Bracco

Microcirculation, cardiac

Phospholipid

Perfluorocarbon

Phase III

Imagify

Acusphere

Cardiac

Poly-L-lactide co-glycide

Perflubutane

Phase III

Sonavist/Sonovist

GE Healthcare

Uptake by Kupffer cells in RES

Polycyanoacrylate

Air

RND

Echogen

Sonus

Heart

Surfactant

Dodecafluoropentane

European approval then withdrawn from market in 2000

  1. aLabeled indications may vary in different in countries/continents. Some CM are not even available in certain countries
  2. bIndia, North America, Australia and New Zealand, parts of the Pacific Rim, and several countries in the Middle East. RND research and development

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von Tengg-Kobligk, H., Mehndiratta, A., Giesel, F.L. (2014). Contrast Agents in Radiology. In: Miller, C., Krasnow, J., Schwartz, L. (eds) Medical Imaging in Clinical Trials. Springer, London. https://doi.org/10.1007/978-1-84882-710-3_15

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