MRI contrast agent

MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI).[1] The most commonly used compounds for contrast enhancement are gadolinium-based. Such MRI contrast agents shorten the relaxation times of nuclei within body tissues following oral or intravenous administration.

In MRI scanners, sections of the body are exposed to a strong magnetic field causing primarily the hydrogen nuclei ("spins") of water in tissues to be polarized in the direction of the magnetic field. An intense radiofrequency pulse is applied that tips the magnetization generated by the hydrogen nuclei in the direction of the receiver coil where the spin polarization can be detected. Random molecular rotational oscillations matching the resonance frequency of the nuclear spins provide the "relaxation" mechanisms that bring the net magnetization back to its equilibrium position in alignment with the applied magnetic field. The magnitude of the spin polarization detected by the receiver is used to form the MR image but decays with a characteristic time constant known as the T1 relaxation time. Water protons in different tissues have different T1 values, which is one of the main sources of contrast in MR images. A contrast agent usually shortens, but in some instances increases, the value of T1 of nearby water protons thereby altering the contrast in the image.

Most clinically used MRI contrast agents work by shortening the T1 relaxation time of protons inside tissues via interactions with the nearby contrast agent. Thermally driven motion of the strongly paramagnetic metal ions in the contrast agent generate the oscillating magnetic fields that provide the relaxation mechanisms that enhance the rate of decay of the induced polarization. The systematic sampling of this polarization over the spatial region of the tissue being examined forms the basis for construction of the image.

MRI contrast agents may be administered by injection into the blood stream or orally, depending on the subject of interest. Oral administration is well suited to G.I. tract scans, while intravascular administration proves more useful for most other scans.

MRI contrast agents can be classified[2] by their:

  • chemical composition
  • administration route
  • magnetic properties
  • biodistribution and applications:
    • Extracellular fluid agents (intravenous contrast agents)
    • Blood pool agents (intravascular contrast agents)
    • Organ specific agents (gastrointestinal contrast agents and hepatobiliary contrast agents)
    • Active targeting/cell labeling agents (tumor-specific agents)
    • Responsive (smart or bioactivated) agents
    • pH-sensitive agents

Gadolinium(III)

Effect of contrast agent on images: Defect of the blood–brain barrier after stroke shown in MRI. T1-weighted images, left image without, right image with contrast medium administration

Gadolinium(III) containing MRI contrast agents (often termed simply "gado" or "gad") are the most commonly used for enhancement of vessels in MR angiography or for brain tumor enhancement associated with the degradation of the blood–brain barrier.[3][4] For large vessels such as the aorta and its branches, the dose can be as low as 0.1 mmol / kg of body mass. Higher concentrations are often used for finer vasculature.[5] Gd3+ chelates are hydrophilic and do not pass the intact blood–brain barrier. Thus, they are useful in enhancing lesions and tumors where blood-brain barrier is compromised and the Gd(III) leaks out. In the rest of the body, the Gd3+ initially remains in the circulation but then distributes into the interstitial space or is eliminated by the kidneys.

Available GBCAs (brand names, approved for human use by EMA[6] | FDA[7] (standard dose[8])):

Extracellular fluid agents

  • Macrocyclic
    • ionic
      • gadoterate (Dotarem, Clariscan) : EMA FDA (SD: 0.1 mmol/kg)
    • non-ionic
      • gadobutrol (Gadovist [EU] / Gadavist [US]) EMA FDA (SD: 0.1 mmol/kg)
      • gadoteridol (ProHance) : EMA FDA (SD: 0.1 mmol/kg)
  • Linear (suspended by EMA[9])
    • ionic
      • gadopentetate (Magnevist, EU: Magnegita, Gado-MRT ratiopharm) FDA (SD: 0.1 mmol/kg))
      • gadobenate (MultiHance) : FDA EMA (liver) (SD: 0.1 mmol/kg)
      • gadopentetic acid dimeglumine (Magnetol)
      • gadoxentate (Eovist, EU: Primovist) FDA
    • non-ionic

Blood pool agents

  • Albumin-binding gadolinium complexes
    • gadofosveset (Ablavar, formerly Vasovist) FDA (SD: 0.03 mmol/kg)
    • gadocoletic acid
  • Polymeric gadolinium complexes
    • gadomelitol
    • gadomer 17

Hepatobiliary (liver) agents

  • gadoxetic acid (Primovist [EU] / Eovist [US]) is used as a hepatobiliary agent as 50% is taken up and excreted by the liver and 50% by the kidneys.

Safety

As a free solubilized aqueous ion, gadolinium (III) is highly toxic, but chelated compound are generally regarded as safe enough to be administered. Free Gd3+ has a median lethal dose of 0.34 mmol/kg (IV, mouse)[10] or 100–200 mg/kg, but the LD50 is increased by a factor of 50 when Gd3+ is chelated.[11]

The use of Gd3+ chelates in persons with acute or chronic kidney can cause nephrogenic systemic fibrosis (NSF),[12][13][14] a rare but severe systemic disease resembling scleromyxedema and to some extent scleroderma. It may occur months after contrast injection.[15] Patients with deteriorated kidney function are more at risk for NSF, with dialysis patients being more at risk than patients with chronic kidney disease.[16][17] NSF can be caused by linear and macrocyclic[18][19] (macrocyclic ionic compounds have been found the least likely to release the Gd3+),[20][12] gadolinium-containing MRI contrast agents although much more frequently by linear.

Gadolinium has been found to remain in the brain, heart muscle, kidney, liver and other organs after one or more injection of a linear or macrocyclic[21][22] GBCA, even after a prolonged period of time. The amount differs with the presence of kidney injury at the moment of injection, the molecular geometry of the ligand and the dose administered.

In vitro studies have found GBCAs to be neurotoxic,[23] and a study found signal intensity in the dentate nucleus of MRI (indicative of gadolinium deposition) to be correlated with lower verbal fluency.[24] Confusion is often reported as a possible clinical symptoms.[23] The FDA has asked doctors to limit the use of Gadolinium contrast agents only when necessary information is made available through its use.[25] Intrathecal injections of doses higher than 1 mmol are associated with severe neurological complications and can lead to death[26] · .[27] The glymphatic system could be the main access of GBCA to the brain in intravenous injection.[28][29]

Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, has led to a safety review by the Committee for Medicinal Products for Human Use (CHMP) which led the EMA to suspend linear gadolinium-based media, in which Gd3+ has a lower binding affinity, in 2017.[9]

In the United States, the research has led the FDA to revise its class warnings for all gadolinium-based contrast media. It is advised that the use of gadolinium-based media is based on careful consideration of the retention characteristics of the contrast. Extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. Minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, do not avoid or defer necessary GBCA MRI scans.[30]

In December 2017, the FDA announced in a drug safety communication it is requiring these new warnings to be included on all GBCAs. The FDA also called for increased patient education and requiring gadolinium contrast vendors to conduct additional animal and clinical studies to assess the safety of these agents.[31]

The French health authority recommends to use the lowest possible dose of a GBCA and only when essential diagnostic information cannot be obtained without it.[32]

The World Health Organization issued a restriction on use of several gadolinium contrast agents in November 2009 stating that "High-risk gadolinium-containing contrast agents (Optimark, Omniscan, Magnevist, Magnegita, and Gado-MRT ratiopharm) are contraindicated in patients with severe kidney problems, in patients who are scheduled for or have recently received a liver transplant, and in newborn babies up to four weeks of age."[33]

In magnetic resonance imaging in pregnancy, gadolinium contrast agents in the first trimester is associated with a slightly increased risk of a childhood diagnosis of several forms of rheumatism, inflammatory disorders, or infiltrative skin conditions, according to a retrospective study including 397 infants prenatally exposed to gadolinium contrast.[34] In the second and third trimester, gadolinium contrast is associated with a slightly increased risk of stillbirth or neonatal death, by the same study.[34]

Anaphylactoid reactions are rare, occurring in about 0.03–0.1%.

Iron oxide: superparamagnetic

Two types of iron oxide contrast agents exist: superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO). These contrast agents consist of suspended colloids of iron oxide nanoparticles and when injected during imaging reduce the T2 signals of absorbing tissues. SPIO and USPIO contrast agents have been used successfully in some instances for liver tumor enhancement.[35]

  • Feridex I.V. (also known as Endorem and ferumoxides). This product was discontinued by AMAG Pharma in November 2008.[36]
  • Resovist (also known as Cliavist). This was approved for the European market in 2001, but production was abandoned in 2009.[37]
  • Sinerem (also known as Combidex). Guerbet withdrew the marketing authorization application for this product in 2007.[38]
  • Lumirem (also known as Gastromark). Gastromark was approved by the FDA in 1996[39] and was discontinued by its manufacturer in 2012.[40][41]
  • Clariscan (also known as PEG-fero, Feruglose, and NC100150). This iron based contrast agent was never commercially launched and its development was discontinued in early 2000s due to safety concerns.[42] In 2017 GE Healthcare launched a macrocyclic extracellular gadolinium based contrast agent containing gadoteric acid as gadoterate meglumine under the trade name Clariscan.[43]

Iron platinum: superparamagnetic

Superparamagnetic iron–platinum particles (SIPPs) have been reported and had significantly better T2 relaxivities compared with the more common iron oxide nanoparticles. SIPPs were also encapsulated with phospholipids to create multifunctional SIPP stealth immunomicelles that specifically targeted human prostate cancer cells.[44] These are, however, investigational agents which have not yet been tried in humans. In a recent study, multifunctional SIPP micelles were synthesized and conjugated to a monoclonal antibody against prostate-specific membrane antigen.[44] The complex specifically targeted human prostate cancer cells in vitro, and these results suggest that SIPPs may have a role in the future as tumor-specific contrast agents.

Manganese

Manganese(II) chelates such as Mn-DPDP (Mangafodipir) enhance the T1 signal.[45] The chelate dissociates in vivo into manganese and DPDP where the former is absorbed intra-cellularly and excreted in bile, while the latter is eliminated via the kidney filtration.[46] Mangafodipir has been used in human neuroimaging clinical trials, with relevance to neurodegenerative diseases such as Multiple Sclerosis.[47][48] Manganese(II) ions are often used as a contrast agent in animal studies, usually referred to as MEMRI (Manganese Enhanced MRI).[49] Due to the ability of Mn2+ to enter cells through calcium transport channels it has been used for functional brain imaging.[50]

Manganese(III) chelates with porphyrins and phthalocyanines and have also be studied.[45]

Unlike the other well-studied iron oxide-based nanoparticles, research on Mn-based nanoparticles is at a relatively early stage.[51]

Oral administration of contrast agents

A wide variety of oral contrast agents can enhance images of the gastrointestinal tract. They include gadolinium and manganese chelates, or iron salts for T1 signal enhancement. SPIO, barium sulfate, air and clay have been used to lower T2 signal. Natural products with high manganese concentration such as blueberry and green tea can also be used for T1 increasing contrast enhancement.[52]

Perflubron, a type of perfluorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging.[53] This contrast agent works by reducing the number of hydrogen ions in a body cavity, thus causing it to appear dark in the images.

Protein-based MRI contrast agents

Newer research suggests the possibility of protein based contrast agents, based on the abilities of some amino acids to bind with gadolinium.[54][55][56][57]

See also

  • Lanthanide probes

References

  1. ↑ Rinck, Peter A. (2022). Magnetic Resonance Contrast Agents. in: Magnetic Resonance in Medicine. A Critical Introduction. 12th edition. Offprint to download: TRTF - The Round Table Foundation / EMRF - European Magnetic Resonance Forum. ISBN 978-3-7460-9518-9.
  2. ↑ Geraldes, Carlos F.G.C.; Laurent, Sophie (2009). "Classification and basic properties of contrast agents for magnetic resonance imaging". Contrast Media & Molecular Imaging. 4 (1): 1–23. doi:10.1002/cmmi.265. PMID 19156706.
  3. ↑ Tircsó, Gyulia; Molńar, Enricő; Csupász, Tibor; Garda, Zoltan; Botár, Richárd; Kálmán, Ferenc K.; Kovács, Zoltan; Brücher, Ernő; Tóth, Imre (2021). "Chapter 2. Gadolinium(III)-Based Contrast Agents for Magnetic Resonance Imaging. A Re-Appraisal". Metal Ions in Bio-Imaging Techniques. Springer. pp. 39–70. doi:10.1515/9783110685701-008. S2CID 233702931.
  4. ↑ McLeod, Shauanna M.; Mead, Thomas J. (2021). "Chapter 12. Magnetic Resonance Theranostics: An Overview of Gadolinium(II)-Bases Strategies and Magnitic Particle Imaging". Metal Ions in Bio-Imaging Techniques. Springer. pp. 347–370. doi:10.1515/9783110685701-018. S2CID 233710460.
  5. ↑ Lentschig, M.G.; Reimer, P.; Rausch-Lentschig, U.L.; Allkemper, T.; Oelerich, M.; Laub, G. (1998). "Breath-hold gadolinium-enhanced MR angiography of the major vessels at 1.0 T: Dose-response findings and angiographic correlation". Radiology. 208 (2): 353–57. doi:10.1148/radiology.208.2.9680558. PMID 9680558.
  6. ↑ "EMA recommendations on Gadolinium-containing contrast agents". ema.europa.eu. Retrieved 2018-07-12.
  7. ↑ "Information on Gadolinium-Containing Contrast Agents". Fda.gov. Retrieved 2018-07-12.
  8. ↑ https://www.radiology.wisc.edu/wp-content/uploads/2017/10/gadolinium-based-contrast-dosing-charts.pdf
  9. 1 2 https://www.ema.europa.eu/en/news/emas-final-opinion-confirms-restrictions-use-linear-gadolinium-agents-body-scans. {{cite web}}: Missing or empty |title= (help)CS1 maint: url-status (link)
  10. ↑ Bousquet et coll., 1988
  11. ↑ Penfield, Jeffrey G.; Reilly, Robert F. (2007). "What nephrologists need to know about gadolinium". Nature Clinical Practice Nephrology. 3 (12): 654–68. doi:10.1038/ncpneph0660. PMID 18033225. S2CID 22435496.
  12. 1 2 Grobner, T. (2005). "Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?". Nephrology Dialysis Transplantation. 21 (4): 1104–08. doi:10.1093/ndt/gfk062. PMID 16431890.
  13. ↑ Marckmann, P.; Skov, L.; Rossen, K.; Dupont, A.; Damholt, M.B.; Heaf, J.G.; Thomsen, H.S. (2006). "Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging". Journal of the American Society of Nephrology. 17 (9): 2359–62. doi:10.1681/ASN.2006060601. PMID 16885403.
  14. ↑ Centers for Disease Control and Prevention (CDC) (2007). "Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents". MMWR. Morbidity and Mortality Weekly Report. 56 (7): 137–41. PMID 17318112.
  15. ↑ Thomsen, H.S.; Morcos, S.K.; Dawson, P. (2006). "Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)?". Clinical Radiology. 61 (11): 905–06. doi:10.1016/j.crad.2006.09.003. PMID 17018301.
  16. ↑ Kanal, E.; Barkovich, A.J.; Bell, C.; Borgstede, J.P.; Bradley, W.G.; Froelich, J.W.; Gilk, T.; Gimbel, J.R.; et al. (2007). "ACR Guidance Document for Safe MR Practices: 2007". American Journal of Roentgenology. 188 (6): 1447–74. doi:10.2214/AJR.06.1616. PMID 17515363.
  17. ↑ "Gadolinium and NSF What is fact and what is theory?". 2008.
  18. ↑ Lim, Yu Jeong; Bang, Jisun; Ko, Youngsun; Seo, Hyun Min; Jung, Woon Yong; Yi, Joo Hark; Han, Sang Woong; Yu, Mi Yeon (2020-09-07). "Late Onset Nephrogenic Systemic Fibrosis in a Patient with Stage 3 Chronic Kidney Disease: a Case Report". Journal of Korean Medical Science. 35 (35): e293. doi:10.3346/jkms.2020.35.e293. ISSN 1598-6357. PMC 7476800. PMID 32893521.
  19. ↑ Elmholdt, Tina Rask; Jørgensen, Bettina; Ramsing, Mette; Pedersen, Michael; Olesen, Anne Braae (June 2010). "Two cases of nephrogenic systemic fibrosis after exposure to the macrocyclic compound gadobutrol". NDT Plus. 3 (3): 285–287. doi:10.1093/ndtplus/sfq028. ISSN 1753-0784. PMC 5477958. PMID 28657062.
  20. ↑ "Questions and Answers" (PDF). International Society for Magnetic Resonance in Medicine.
  21. ↑ Stanescu, A. Luana; Shaw, Dennis W.; Murata, Nozomu; Murata, Kiyoko; Rutledge, Joe C.; Maloney, Ezekiel; Maravilla, Kenneth R. (March 2020). "Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: pathological confirmation". Pediatric Radiology. 50 (3): 388–396. doi:10.1007/s00247-019-04535-w. ISSN 1432-1998. PMID 31989188. S2CID 210913930.
  22. ↑ Bussi, Simona; Coppo, Alessandra; Celeste, Roberto; Fanizzi, Antonello; Fringuello Mingo, Alberto; Ferraris, Andrea; Botteron, Catherine; Kirchin, Miles A.; Tedoldi, Fabio; Maisano, Federico (2020-02-04). "Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats". Insights into Imaging. 11 (1): 11. doi:10.1186/s13244-019-0824-5. ISSN 1869-4101. PMC 7000570. PMID 32020385.
  23. 1 2 Bower, Danielle V.; Richter, Johannes K.; von Tengg-Kobligk, Hendrik; Heverhagen, Johannes T.; Runge, Val M. (August 2019). "Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent". Investigative Radiology. 54 (8): 453–463. doi:10.1097/RLI.0000000000000567. ISSN 1536-0210. PMID 31265439. S2CID 164486744.
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  28. ↑ Taoka, Toshiaki; Naganawa, Shinji (2018-04-10). "Gadolinium-based Contrast Media, Cerebrospinal Fluid and the Glymphatic System: Possible Mechanisms for the Deposition of Gadolinium in the Brain". Magnetic resonance in medical sciences: MRMS: an official journal of Japan Society of Magnetic Resonance in Medicine. 17 (2): 111–119. doi:10.2463/mrms.rev.2017-0116. ISSN 1880-2206. PMC 5891336. PMID 29367513. Retrieved 2021-08-20..
  29. ↑ https://www.guerbet.com/en-us/webinar-bhatia-gbcas/. {{cite web}}: Missing or empty |title= (help)
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  32. ↑ "GADOLINIUM PIC RI REEVAL RAPPORT ANNEXE". www.has-sante.fr. Retrieved 2021-08-19.
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  34. 1 2 Mervak, Benjamin M.; Altun, Ersan; McGinty, Katrina A.; Hyslop, W. Brian; Semelka, Richard C.; Burke, Lauren M. (2019). "MRI in pregnancy: Indications and practical considerations". Journal of Magnetic Resonance Imaging. 49 (3): 621–31. doi:10.1002/jmri.26317. ISSN 1053-1807. PMID 30701610. S2CID 73412175.
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  42. ↑ Wang, Yi-Xiang J. (2011). "Superparamagnetic iron oxide based MRI contrast agents: Current status of clinical application". Quantitative Imaging in Medicine and Surgery. 1 (1): 35–40. doi:10.3978/j.issn.2223-4292.2011.08.03. PMC 3496483. PMID 23256052.
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  44. 1 2 Taylor, Robert M.; Huber, Dale L.; Monson, Todd C.; Ali, Abdul-Mehdi S.; Bisoffi, Marco; Sillerud, Laurel O. (2011). "Multifunctional iron platinum stealth immunomicelles: Targeted detection of human prostate cancer cells using both fluorescence and magnetic resonance imaging". Journal of Nanoparticle Research. 13 (10): 4717–29. Bibcode:2011JNR....13.4717T. doi:10.1007/s11051-011-0439-3. PMC 3223933. PMID 22121333.
  45. 1 2 Lacerda, Sara; Ndiaye, Daouda; Tóth, Éva (2021). "Chapter 3. Manganese Complexes as Contrast Agents for Magnetic Resonance Imaging". Metal Ions in Bio-Imaging Techniques. Springer. pp. 71–99. doi:10.1515/9783110685701-009. S2CID 233682771.
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  51. ↑ Zhen, Zipeng; Xie, J (2012). "Development of Manganese-Based Nanoparticles as Contrast Probes for Magnetic Resonance Imaging". Theranostics. 2 (1): 45–54. doi:10.7150/thno.3448. PMC 3263515. PMID 22272218.
  52. ↑ Lee, Joseph K.T. (2006). Computed Body Tomography with MRI Correlation. ISBN 978-0-7817-4526-0.
  53. ↑ Bisset, G.S.; Emery, K.H.; Meza, M.P.; Rollins, N.K.; Don, S.; Shorr, J.S. (1996). "Perflubron as a gastrointestinal MR imaging contrast agent in the pediatric population". Pediatric Radiology. 26 (6): 409–15. doi:10.1007/BF01387316. PMID 8657479. S2CID 10032242.
  54. ↑ Xue, Shenghui; Qiao, Jingjuan; Pu, Fan; Cameron, Mathew; Yang, Jenny J. (2013). "Design of a novel class of protein-based magnetic resonance imaging contrast agents for the molecular imaging of cancer biomarkers". Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology. 5 (2): 163–79. doi:10.1002/wnan.1205. PMC 4011496. PMID 23335551.
  55. ↑ Li, Shunyi; Jiang, Jie; Zou, Jin; Qiao, Jingjuan; Xue, Shenghui; Wei, Lixia; Long, Robert; Wang, Liya; et al. (2012). "PEGylation of protein-based MRI contrast agents improves relaxivities and biocompatibilities". Journal of Inorganic Biochemistry. 107 (1): 111–18. doi:10.1016/j.jinorgbio.2011.11.004. PMC 3273044. PMID 22178673.
  56. ↑ Xue, Shenghui; Qiao, Jingjuan; Hubbard, Kendra; White, Natalie; Wei, Lixia; Li, Shunyi; Liu, Zhi-Reb; Yang, Jenny J; Yang, J.J. (2014). "Design of ProCAs (Protein-Based Gd3+ MRI Contrast Agents) with High Dose Efficiency and Capability for Molecular Imaging of Cancer Biomarkers". Medicinal Research Reviews. 34 (5): 1070–99. doi:10.1002/med.21313. PMID 24615853. S2CID 42641594.
  57. ↑ Qiao, Jingjuan; Xue, Shenghui; Pu, Fan; White, Natalie; Liu, Zhi-Ren; Yang, Jenny J. (2014). "Molecular imaging of EGFR/HER2 cancer biomarkers by protein MRI contrast agents". J Biol Inorg Chem. 19 (2): 259–70. doi:10.1007/s00775-013-1076-3. PMC 3931309. PMID 24366655.
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