MRI contrast agent#Gadolinium

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 gastrointestinal tract scans, while intravascular administration proves more useful for most other scans.

MRI contrast agents can be classified{{cite journal |last1=Geraldes |first1=Carlos F.G.C. |last2=Laurent |first2=Sophie |year=2009 |title=Classification and basic properties of contrast agents for magnetic resonance imaging |journal=Contrast Media & Molecular Imaging |volume=4 |issue=1 |pages=1–23 |doi=10.1002/cmmi.265 |doi-access=free |pmid=19156706}} 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) ==

File:Bluthirnschranke nach Infarkt nativ und KM.png

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 (BBB).{{cite book |first1=Gyulia |last1=Tircsó |first2=Enricő |last2=Molńar |first3=Tibor |last3=Csupász |first4=Zoltan |last4=Garda |first5=Richárd |last5=Botár |first6=Ferenc K. |last6=Kálmán|first7=Zoltan |last7=Kovács |first8=Ernő |last8=Brücher |first9=Imre |last9=Tóth |year=2021 |chapter=Chapter 2. Gadolinium(III)-based contrast agents for magnetic resonance imaging: A re-appraisal |title=Metal Ions in Bio-Imaging Techniques |publisher=Springer |pages=39–70 |doi=10.1515/9783110685701-008 |s2cid=233702931}}{{cite book |first1=Shauanna M. |last1=McLeod |first2=Thomas J. |last2=Mead |year=2021 |chapter=Chapter 12. Magnetic resonance theranostics: An overview of gadolinium(II)-based strategies and magnetic particle imaging |title=Metal Ions in Bio-Imaging Techniques|publisher=Springer |pages=347–370 |doi=10.1515/9783110685701-018 |s2cid=233710460}} Over 450 million doses have been administered worldwide from 1988 to 2017.{{cite report |author=Balzer, T. |year=2017 |section=Presence of gadolinium (Gd) in the brain and body |title=Bayer presentation to the September 8, 2017 meeting of the Medical Imaging Drugs Advisory Committee |publisher=Bayer HealthCare Pharmaceuticals Inc. |publication-place=Silver Spring, MD |url=https://www.fda.gov/files/advisory%20committees/published/Bayer-Presentation-for-the-September-8--2017-Meeting-of-the-Medical-Imaging-Drugs-Advisory-Committee.pdf |access-date=2022-04-01 |via=US FDA}} For large vessels such as the aorta and its branches, the dose can be as low as {{nobr|0.1 mmol/kg}} of body mass. Higher concentrations are often used for finer vasculature.{{cite journal |last1=Lentschig |first1=M.G. |last2=Reimer |first2=P. |last3=Rausch-Lentschig |first3=U.L. |last4=Allkemper |first4=T. |last5=Oelerich |first5=M. |last6=Laub |first6=G. |year=1998 |title=Breath-hold gadolinium-enhanced MR angiography of the major vessels at 1.0 T: Dose-response findings and angiographic correlation |volume=208 |issue=2 |pages=353–357 |journal=Radiology |pmid=9680558 |doi=10.1148/radiology.208.2.9680558}} At much higher concentration, there is more T2 shortening effect of gadolinium, causing gadolinium brightness to be less than surrounding body tissues.{{cite journal | vauthors = Lee MJ, Kim MJ, Yoon CS, Song SY, Park K, Kim WS | year = 2011 | title = The T2-shortening effect of gadolinium and the optimal conditions for maximizing the CNR for evaluating the biliary system: a phantom study | journal = Korean Journal of Radiology | volume = 12 | issue = 3 | pages = 358–364 | pmid = 21603295 | pmc = 3088853 | doi = 10.3348/kjr.2011.12.3.358 }} However at such concentration, it will cause greater toxicity to bodily tissues.{{cite journal | vauthors = Xiao YD, Paudel R, Liu J, Ma C, Zhang ZS, Zhou SK | date = November 2016 | title = MRI contrast agents: Classification and application (Review) | journal = International Journal of Molecular Medicine | volume = 38 | issue = 5 | pages = 1319–1326 | pmid = 27666161 | doi = 10.3892/ijmm.2016.2744 | doi-access = free }}

Gd³⁺ chelates are hydrophilic and do not readily cross the intact blood–brain barrier. Thus, they are useful in enhancing lesions and tumors where the blood–brain barrier is compromised and the Gd(III) leaks out.{{cite journal |vauthors=Bagnato F, Gauthier SA, Laule C, Moore G, Bove R, Cai Z, Cohen-Adad J, Harrison DM, Klawiter EC, Morrow SA, Öz G, Rooney WD, Smith SA, Calabresi PA, Henry RG, Oh J, Ontaneda D, Pelletier D, Reich DS, Shinohara RT, Sicotte NL |display-authors=6 |date=May 2020 |title=Imaging mechanisms of disease progression in multiple sclerosis: Beyond brain atrophy |journal=Journal of Neuroimaging |volume=30 |issue=3 |pages=251–266 |pmid=32418324 |doi=10.1111/jon.12700|s2cid=218677556 }}{{efn|

"Disruption of the BBB tight junctions is thought to be an early or initiating event in new MS lesion formation. T1-w MRI in combination with low molecular weight gadolinium-based contrast agents (GBCA) is most typically used to characterize BBB compromise in MS. MRI GBCAs do not readily cross cellular membranes, are avid extracellular space markers, and are thought to enter the brain from the blood by diffusive transport between endothelial cells (ie, via intercellular pathways). Although it is widely believed that the MRI GBCAs do not cross the BBB under homeostatic conditions, there is substantial evidence that they do, albeit with very small volume transfer rate {{nobr|constants." — Bagnato, Gauthier, Laule, et al. (2020)}}

}} 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 gadolinium-based contrast agents (GBCAs) (brand names, approved for human use by EMA{{cite report |title=EMA recommendations on gadolinium-containing contrast agents |publisher=European Medicines Agency |website=ema.europa.eu |url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Gadolinium-containing_contrast_agents/human_referral_prac_000056.jsp&mid=WC0b01ac05805c516f |access-date=2018-07-12}}{{When|reason=when was it first approved by EMA?|date=April 2022}} and by the FDA in 1988;{{cite journal |last=Kanal |first=Emanuel |date=Dec 2016 |title=Gadolinium based contrast agents (GBCA): Safety overview after 3 decades of clinical experience |journal=Magnetic Resonance Imaging |volume=34 |issue=10 |pages=1341–1345 |doi=10.1016/j.mri.2016.08.017 |issn=1873-5894 |pmid=27608608 |url=https://pubmed.ncbi.nlm.nih.gov/27608608}}{{cite report |title=Information on gadolinium-containing contrast agents |series=Post-market Drug Safety Information for Patients and Providers |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm142882.htm |access-date=2018-07-12 |via=fda.gov}} (standard dose{{cite web |title=Gadolinium Based Contrast Dosing Charts |url=https://www.radiology.wisc.edu/wp-content/uploads/2017/10/gadolinium-based-contrast-dosing-charts.pdf}})):

• Macrocyclic
• ionic
• gadoterate (Dotarem, Clariscan): EMA, FDA ({{nobr|{{abbr|SD|Standard dose}}: 0.1 mmol/kg}}){{cite journal |last1=McDonald |first1=Robert J. |last2=Levine |first2=Deborah |last3=Weinreb |first3=Jeffrey |last4=Kanal |first4=Emanuel |last5=Davenport |first5=Matthew S. |last6=Ellis |first6=James H. |last7=Jacobs |first7=Paula M. |last8=Lenkinski |first8=Robert E. |last9=Maravilla |first9=Kenneth R. |last10=Prince |first10=Martin R. |last11=Rowley |first11=Howard A. |date=November 2018 |title=Gadolinium retention: A research roadmap from the 2018 NIH / ACR / RSNA workshop on gadolinium chelates |journal=Radiology |language=en |volume=289 |issue=2 |pages=517–534 |doi=10.1148/radiol.2018181151 |issn=0033-8419 |pmc=6209069 |pmid=30204075}}
• non-ionic
• gadobutrol (Gadovist [EU] / Gadavist [US]): EMA, FDA ({{nobr|SD: 0.1 mmol/kg}})
• gadoteridol (ProHance): EMA, FDA ({{nobr|SD: 0.1 mmol/kg}})
• gadopiclenol (Elucirem, Vueway): EMA, FDA ({{nobr|SD: 0.05 mmol/kg}}){{cite web | title=Elucirem- gadopiclenol injection | website=DailyMed | date=12 October 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ca582f31-1042-487f-82e4-533f1b541902 | access-date=16 October 2022 | archive-date=16 October 2022 | archive-url=https://web.archive.org/web/20221016202507/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ca582f31-1042-487f-82e4-533f1b541902 | url-status=live }}
• Linear (suspended by EMA{{cite press release |title=EMAs final opinion confirms restrictions on the use of linear gadolinium agents |date=17 September 2018 |website=ema.europa.eu |publisher=European Medicines Agency |url=https://www.ema.europa.eu/en/news/emas-final-opinion-confirms-restrictions-use-linear-gadolinium-agents-body-scans }})
• ionic
• gadopentetate (Magnevist, EU: Magnegita, Gado-MRT ratiopharm): FDA ({{nobr|SD: 0.1 mmol/kg}})
• gadobenate (MultiHance): FDA, EMA (liver) ({{nobr|SD: 0.1 mmol/kg}})
• gadopentetic acid dimeglumine (Magnetol)
• gadoxetate (Eovist, EU: Primovist): FDA ({{nobr|SD: 0.025 mmol/kg}})
• non-ionic
• gadoversetamide (OptiMARK): FDA ({{nobr|SD: 0.1 mmol/kg}})
• gadodiamide (Omniscan): FDA ({{nobr|SD: 0.1 mmol/kg}})

• Albumin-binding gadolinium complexes
• gadofosveset (Ablavar, formerly Vasovist): FDA ({{nobr|SD: 0.1 mmol/kg}})
• gadocoletic acid
• Polymeric gadolinium complexes
• gadomelitol
• gadomer 17

• 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.

{{update section|date=August 2021}}

{{main|Nephrogenic systemic fibrosis}}

The use of Gd³⁺ chelates in persons with acute or chronic kidney disease can cause nephrogenic systemic fibrosis (NSF),{{cite journal |last1=Grobner |first1=T. |year=2005 |title=Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? |journal=Nephrology Dialysis Transplantation |volume=21 |issue=4 |pages=1104–1108 |doi=10.1093/ndt/gfk062 |doi-access=free |pmid=16431890}}{{cite journal |last1=Marckmann |first1=P. |last2=Skov |first2=L. |last3=Rossen |first3=K. |last4=Dupont |first4=A. |last5=Damholt |first5=M.B. |last6=Heaf |first6=J.G. |last7=Thomsen |first7=H.S. |year=2006 |title=Nephrogenic systemic fibrosis: Suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging |journal=Journal of the American Society of Nephrology |volume=17 |issue=9 |pages=2359–2362 |doi=10.1681/ASN.2006060601 |doi-access=free |pmid=16885403}}{{cite journal |publisher=Centers for Disease Control and Prevention (CDC) |year=2007 |title=Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents |journal=Morbidity and Mortality Weekly Report |volume=56 |issue=7 |pages=137–141 |pmid=17318112 |author1=Centers for Disease Control and Prevention (CDC) }} a rare but severe systemic disease resembling scleromyxedema and to some extent scleroderma. It may occur months after contrast injection.{{cite journal |last1=Thomsen |first1=H.S. |last2=Morcos |first2=S.K. |last3=Dawson |first3=P. |year=2006 |title=Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? |journal=Clinical Radiology |volume=61 |issue=11 |pages=905–906 |pmid=17018301 |doi=10.1016/j.crad.2006.09.003}} Patients with severely deteriorated kidney function are more at risk for NSF, with dialysis patients being more at risk than patients with mild chronic kidney disease.{{cite journal |last1=Kanal |first1=E. |last2=Barkovich |first2=A.J. |last3=Bell |first3=C. |last4=Borgstede |first4=J.P. |last5=Bradley |first5=W.G. |last6=Froelich |first6=J.W. |last7=Gilk |first7=T. |last8=Gimbel |first8=J.R. |last9=Gosbee |first9=J. |last10=Kuhni-Kaminski |first10=Ellisa |last11=Lester |first11=James W. |last12=Nyenhuis |first12=John |last13=Parag |first13=Yoav |last14=Schaefer |first14=Daniel J. |last15=Sebek-Scoumis |first15=Elizabeth A. |last16=Weinreb |first16=Jeffrey |last17=Zaremba |first17=Loren A. |last18=Wilcox |first18=Pamela |last19=Lucey |first19=Leonard |last20=Sass |first20=Nancy |collaboration=ACR Blue Ribbon Panel on MR Safety |display-authors=6 |year=2007 |title=ACR Guidance Document for Safe MR Practices: 2007 |journal=American Journal of Roentgenology |volume=188 |issue=6 |pages=1447–1474 |pmid=17515363 |doi=10.2214/AJR.06.1616 }}{{cite web |title=Gadolinium and NSF: What is fact and what is theory? |year=2008 |website=c2i2.org |id=volume vi, issue 2 |url=http://www.c2i2.org/vol_vi_issue_2/Gadolinium_and_NSF%20-What_is_fact_and_what_is_theory.asp |archive-url=https://archive.today/20090316043147/http://www.c2i2.org/vol_vi_issue_2/Gadolinium_and_NSF%20-What_is_fact_and_what_is_theory.asp |archive-date=16 March 2009 |url-status=dead|access-date=2023-07-23}} NSF can be caused by linear and macrocyclic gadolinium-containing MRI contrast agents,{{cite journal |last1=Lim |first1=Yu Jeong |last2=Bang |first2=Jisun |last3=Ko |first3=Youngsun |last4=Seo |first4=Hyun Min |last5=Jung |first5=Woon Yong |last6=Yi |first6=Joo Hark |last7=Han |first7=Sang Woong |last8=Yu |first8=Mi Yeon |date=2020-09-07 |title=Late onset nephrogenic systemic fibrosis in a patient with stage 3 chronic kidney disease: A case report |journal=Journal of Korean Medical Science |volume=35 |issue=35 |page=e293 |doi=10.3346/jkms.2020.35.e293 |issn=1598-6357 |pmc=7476800 |pmid=32893521}}{{Cite journal |last1=Elmholdt |first1=Tina Rask |last2=Jørgensen |first2=Bettina |last3=Ramsing |first3=Mette |last4=Pedersen |first4=Michael |last5=Olesen |first5=Anne Braae |date=June 2010 |title=Two cases of nephrogenic systemic fibrosis after exposure to the macrocyclic compound gadobutrol |journal=NDT Plus |volume=3 |issue=3 |pages=285–287 |doi=10.1093/ndtplus/sfq028 |issn=1753-0784 |pmc=5477958 |pmid=28657062}} although macrocyclic ionic compounds have been found the least likely to release the Gd³⁺.{{cite web |title=Questions and Answers |url=http://www.ismrm.org/special/EMEA2.pdf |publisher=International Society for Magnetic Resonance in Medicine}}

While NSF is a severe form of disease, gadolinium deposition disease (GDD) is a mild variant with pain (e.g. headache), fatigue, and / or gadolinium depositions.{{cite journal |vauthors=Boehm IB |year=2022 |title=Gadolinium deposition disease (GDD): Does the missing link exist? – A suggested pathologic model |journal=European Journal of Internal Medicine |volume=105 |issue=11 |pages=118–120 |pmid=35864076 |doi=10.1016/j.ejim.2022.07.008|s2cid=250648810 }}

As a free solubilized aqueous ion, gadolinium(III) is highly toxic, but the chelated compounds are generally regarded as safe for individuals without kidney disease. Free Gd³⁺ has a median lethal dose of {{nobr|0.34 mmol/kg}} (IV, mouse){{cite journal |last=Bousquet |first=JC |display-authors=etal |title=Gd-DOTA: characterization of a new paramagnetic complex |journal=Radiology |date=March 1988 |volume=166 |number=3 |pages=693–8 |doi=10.1148/radiology.166.3.3340763 |PMID=3340763}} or {{nobr|100–200 mg/kg,}} but the LD50 is increased by a factor of 31 times{{cite report |title=Profil toxicologique des chélates de gadolinium pour l'IRM : où en est-on ? |lang=fr |trans-title=Toxicological profile of gadolinium chelates for MRI: where do we stand? |year=2014 |publisher=Academie de pharmacie |website=acadpharm.org |url=https://www.acadpharm.org/dos_public/Academie_de_pharmacie_2014_JM_Idee_V2.pdf}} when Gd³⁺ is chelated.{{cite journal |last1=Penfield |first1=Jeffrey G. |last2=Reilly |first2=Robert F. |year=2007 |title=What nephrologists need to know about gadolinium |journal=Nature Clinical Practice Nephrology |volume=3 |issue=12 |pages=654–668 |pmid=18033225 |doi=10.1038/ncpneph0660 |s2cid=22435496 }}

The spectrum of adverse drug reactions is greater with gadolinium-based contrast agents than with iodinated contrast agents (radiocontrast agents).{{cite journal |vauthors=Boehm IB |year=2022 |title=Classification of gadolinium-based contrast agents (GBCAs) – adverse reactions |journal=Magnetic Resonance Imaging |volume=85 |issue=1 |pages=1–2 |pmid=34662698 |doi=10.1016/j.mri.2021.10.006|s2cid=239027228 |url=https://boris.unibe.ch/160180/ }}

Gadolinium has been found to remain in the brain, heart muscle, kidney, liver, and other organs after one or more injections of a linear or macrocyclic gadolinium-based contrast agents, even after a prolonged period of time.{{cite journal |last1=Stanescu |first1=A. Luana |last2=Shaw |first2=Dennis W. |last3=Murata |first3=Nozomu |last4=Murata |first4=Kiyoko |last5=Rutledge |first5=Joe C. |last6=Maloney |first6=Ezekiel |last7=Maravilla |first7=Kenneth R. |date=March 2020 |title=Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: Pathological confirmation |url=https://pubmed.ncbi.nlm.nih.gov/31989188/|journal=Pediatric Radiology |volume=50 |issue=3 |pages=388–396 |doi=10.1007/s00247-019-04535-w |issn=1432-1998 |pmid=31989188|s2cid=210913930}}{{cite journal |last1=Bussi |first1=Simona |last2=Coppo |first2=Alessandra |last3=Celeste |first3=Roberto |last4=Fanizzi |first4=Antonello |last5=Fringuello Mingo |first5=Alberto |last6=Ferraris |first6=Andrea |last7=Botteron |first7=Catherine |last8=Kirchin |first8=Miles A. |last9=Tedoldi |first9=Fabio |last10=Maisano |first10=Federico |display-authors=6 |date=2020-02-04 |df=dmy-all |title=Macrocyclic MR contrast agents: Evaluation of multiple-organ gadolinium retention in healthy rats |journal=Insights into Imaging |volume=11 |issue=1 |page=11 |doi=10.1186/s13244-019-0824-5 |issn=1869-4101 |pmc=7000570 |pmid=32020385 |doi-access=free }} The amount differs with the presence of kidney injury at the moment of injection, the molecular geometry of the ligand, and the dose administered.{{citation needed|date=May 2023}}

In vitro studies have found gadolinium-based contrast agents to be neurotoxic,{{cite journal |last1=Bower |first1=Danielle V. |last2=Richter |first2=Johannes K. |last3=von Tengg-Kobligk |first3=Hendrik |last4=Heverhagen |first4=Johannes T. |last5=Runge |first5=Val M. |date=August 2019 |title=Gadolinium-based MRI contrast agents induce mitochondrial toxicity and cell death in human neurons, and toxicity increases with reduced kinetic stability of the agent |journal=Investigative Radiology |volume=54 |issue=8 |pages=453–463 |doi=10.1097/RLI.0000000000000567 |issn=1536-0210 |pmid=31265439 |s2cid=164486744 |url=https://pubmed.ncbi.nlm.nih.gov/31265439/}} and a study found signal intensity in the dentate nucleus of MRI (indicative of gadolinium deposition) to be correlated with lower verbal fluency.{{cite journal |last1=Forslin |first1=Y. |last2=Martola |first2=J. |last3=Bergendal |first3=Å. |last4=Fredrikson |first4=S. |last5=Wiberg |first5=M.K. |last6=Granberg |first6=T. |date=August 2019 |title=Gadolinium retention in the brain: An MRI relaxometry study of linear and macrocyclic gadolinium-based contrast agents in multiple sclerosis |journal=American Journal of Neuroradiology |volume=40 |issue=8 |pages=1265–1273 |doi=10.3174/ajnr.A6112 |issn=0195-6108 |pmc=7048491 |pmid=31248867}} Confusion is often reported as a possible clinical symptom. The FDA has asked doctors to limit the use of gadolinium contrast agents to examinations where necessary information is obtained only through its use.{{cite report |title=FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI) |series=FDA Drug Safety Communication |publisher=FDA |date=18 June 2019 |url=https://www.fda.gov/Drugs/DrugSafety/ucm455386.htm}} Intrathecal injections of doses higher than 1 mmol are associated with severe neurological complications and can lead to death.{{cite journal |first1=Mihilkumar |last1=Patel |first2=Almohannad |last2=Atyani |first3=Jean-Paul |last3=Salameh |first4=Matthew |last4=McInnes |date=October 2020 |title=Safety of intrathecal administration of gadolinium-based contrast agents: A systematic review and meta-analysis |journal=Radiology |volume=297 |number=1 |issn=1527-1315 |pmid=32720867 |doi=10.1148/radiol.2020191373 |url=https://pubmed.ncbi.nlm.nih.gov/32720867/ |access-date=2021-08-20 |pages=75–83|s2cid=220842011 }}{{cite journal |first1=David Anthony |last1=Provenzano |first2=Zachary |last2=Pellis |first3=Leonard |last3=DeRiggi |date=2019-04-25 |df=dmy-all |title=Fatal gadolinium-induced encephalopathy following accidental intrathecal administration: A case report and a comprehensive evidence-based review |journal=Regional Anesthesia and Pain Medicine |volume=44 |issue=7 |pages=721–729 |issn=1532-8651 |pmid=31023932 |doi=10.1136/rapm-2019-100422 |s2cid=133608033 |doi-access=free }} The glymphatic system could be the main access of GBCA to the brain in intravenous injection.{{cite journal |first1=Toshiaki |last1=Taoka |first2=Shinji |last2=Naganawa |date=2018-04-10 |title=Gadolinium-based Contrast Media, Cerebrospinal Fluid and the Glymphatic System: Possible Mechanisms for the Deposition of Gadolinium in the Brain |journal=Magnetic Resonance in Medical Sciences |volume=17 |number=2 |pages=111–119 |issn=1880-2206 |pmid=29367513 |pmc=5891336 |doi=10.2463/mrms.rev.2017-0116}}{{cite AV media |year=2019 |people=Dr. Aashim Bhatia (presenter) |title=Webinar on the role of the glymphatic system, and the growing awareness with gadolinium (Gd) deposits found in the brain |medium=video |lang=en |url=https://www.guerbet.com/en-us/webinar-bhatia-gbcas |url-status=live |archive-url=https://web.archive.org/web/20230126164931/https://i.vimeocdn.com/video/1243428210-b4f1ab9cdf908dec853a906033ea2e5fffa24ad5240aa9ff436143f295c53333-d?mw=2400&mh=1313&q=70 |archive-date=January 26, 2023}}

Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, led to a safety review by the Committee for Medicinal Products for Human Use (CHMP) which led the EMA to restrict or suspend authorization for the intravenous use of most brands of linear gadolinium-based media, in which Gd³⁺ has a lower binding affinity, in 2017.https://www.ema.europa.eu/en/medicines/human/referrals/gadolinium-containing-contrast-agents#overview

In the United States, the research has led the FDA to revise its class warnings for gadolinium-based contrast media. It is advised that the use of gadolinium-based media should be based on careful consideration of the retention characteristics of the contrast, with extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. They also advise minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies, but not avoiding or deferring necessary GBCA MRI scans.{{cite web|url=https://www.fda.gov/downloads/Drugs/DrugSafety/UCM589442.pdf|title=FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings|date=2017-12-19|website=United States Food and Drug Administration}} {{PD-notice}}

In December 2017, the FDA announced that it was requiring these 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.{{cite web |title=FDA warns gadolinium based contrast agents gbcas are retained body; requires new class warnings |date=2018-05-16 |website=US FDA |series=FDA Drug Safety Communication |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body}}

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.{{cite report |title=Gadolinium pic RI reeval rapport annexe |lang=fr |trans-title=Gadolinium peak RI re-eval report appendix |website=has-sante.fr |url=https://www.has-sante.fr/plugins/ModuleXitiKLEE/types/FileDocument/doXiti.jsp?id=c_2870309 |access-date=2021-08-19}}

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."{{cite report |title=Pharmaceuticals: Restrictions in use and availability |year=2010 |publisher=World Health Organization |page=14 |url=https://www.who.int/medicines/publications/Restricted_List_FINAL_2010.pdf |via=who.int}}

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.{{cite journal |last1=Mervak |first1=Benjamin M. |last2=Altun |first2=Ersan |last3=McGinty |first3=Katrina A. |last4=Hyslop |first4=W. Brian |last5=Semelka |first5=Richard C. |last6=Burke |first6=Lauren M. |year=2019 |title=MRI in pregnancy: Indications and practical considerations |journal=Journal of Magnetic Resonance Imaging |volume=49 |issue=3 |pages=621–631 |doi=10.1002/jmri.26317 |issn=1053-1807 |pmid=30701610 |s2cid=73412175}} In the second and third trimester, gadolinium contrast is associated with a slightly increased risk of stillbirth or neonatal death, by the same study.

Guidelines from the Canadian Association of Radiologists{{cite journal |vauthors= Schieda N, Blaichman JI, Costa AF, Glikstein R, Hurrell C, James M, Jabehdar Maralani P, Shabana W, Tang A, Tsampalieros A, van der Pol CB, Hiremath S |title= Gadolinium-Based Contrast Agents in Kidney Disease: A Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists |journal= Canadian Journal of Kidney Health and Disease |volume= 5 |pages= 2054358118778573 |date= 2018 |pmid= 29977584 |pmc= 6024496 |doi= 10.1177/2054358118778573}} are that dialysis patients should receive gadolinium agents only where essential and that they should receive dialysis after the exam. If a contrast-enhanced MRI must be performed on a dialysis patient, it is recommended that certain high-risk contrast agents be avoided but not that a lower dose be considered. The American College of Radiology recommends that contrast-enhanced MRI examinations be performed as closely before dialysis as possible as a precautionary measure, although this has not been proven to reduce the likelihood of developing NSF.{{cite book |author1=ACR Committee on Drugs |author2=Contrast Media |title= ACR Manual on Contrast Media Version 7 |date= 2010 |publisher=American College of Radiology |isbn= 978-1-55903-050-2}} The FDA recommends that potential for gadolinium retention be considered when choosing the type of GBCA used in patients requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions.{{cite web|url=https://www.fda.gov/Drugs/DrugSafety/ucm589213.htm|publisher=Drug Safety and Availability – FDA Drug Safety Communication |title=FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings|author=Center for Drug Evaluation and Research|website=www.fda.gov|language=en|access-date=11 February 2025}}

Anaphylactoid reactions are rare, occurring in about 0.03–0.1%.{{cite journal|vauthors=Murphy KJ, Brunberg JA, Cohan RH|date=October 1996|title=Adverse reactions to gadolinium contrast media: a review of 36 cases|journal=AJR. American Journal of Roentgenology|volume=167|issue=4|pages=847–49|doi=10.2214/ajr.167.4.8819369|pmid=8819369|doi-access=free}}

{{main|Superparamagnetic relaxometry}}

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 lesion evaluation.{{cite journal |last1=Nakamura |first1=Hiroshi |last2=Ito |first2=Naoki |last3=Kotake |first3=Fumio |last4=Mizokami |first4=Yuji |last5=Matsuoka |first5=Takeshi |year=2000 |title=Tumor-detecting capacity and clinical usefulness of SPIO-MRI in patients with hepatocellular carcinoma |journal=Journal of Gastroenterology |volume=35 |issue=11 |pages=849–855 |pmid=11085494 |s2cid=1037632 |doi=10.1007/s005350070022}}{{Cite journal |last1=Shahrouki |first1=Puja |last2=Felker |first2=Ely R. |last3=Raman |first3=Steven S. |last4=Jeong |first4=Woo Kyoung |last5=Lu |first5=David S. |last6=Finn |first6=J. Paul |date=2021-10-24 |title=Steady-state ferumoxytol-enhanced MRI: Early observations in benign abdominal organ masses and clinical implications |journal=Abdominal Radiology |volume=47 |issue=1 |pages=460–470 |doi=10.1007/s00261-021-03271-w |pmid=34689252 |pmc=8776683 |issn=2366-004X}}

• Feridex I.V. (also known as Endorem and ferumoxides). This product was discontinued by AMAG Pharma in November 2008.{{cite web |title=Feridex |website=Amagpharma.com |url=http://www.amagpharma.com/products/feridex_iv.php |access-date=2012-06-20 |url-status=dead |archive-url=https://web.archive.org/web/20120615182847/http://www.amagpharma.com/products/feridex_iv.php |archive-date=2012-06-15 }}
• Resovist (also known as Cliavist). This was approved for the European market in 2001, but production was abandoned in 2009.{{cite web |title=Magnetic resonance TIP – MRI database : Resovist |website=Mr-tip.com |publisher=Softways |url=http://www.mr-tip.com/serv1.php?type=db1&dbs=Resovist |access-date=2012-06-20}}
• Sinerem (also known as Combidex). Guerbet withdrew the marketing authorization application for this product in 2007.{{cite web |title=Update on Sinerem (TM) in Europe |date=2007-12-13 |publisher=AMAG Pharmaceuticals |url=http://www.thefreelibrary.com/AMAG+Pharmaceuticals,+Inc.+Announces+Update+on+Sinerem(TM)+in+Europe.-a0172378541 |via=Thefreelibrary.com |access-date=2012-06-20 |archive-date=23 March 2019 |archive-url=https://web.archive.org/web/20190323160818/https://www.thefreelibrary.com/AMAG+Pharmaceuticals%2c+Inc.+Announces+Update+on+Sinerem(TM)+in+Europe.-a0172378541 |url-status=dead }}
• Lumirem (also known as Gastromark). Gastromark was approved by the FDA in 1996{{cite web |title=Newly approved drug therapies (105) GastroMARK (Advanced Magnetics) |publisher=CenterWatch |url=http://www.centerwatch.com/drug-information/fda-approvals/drug-details.aspx?DrugID=105 |url-status=dead |access-date=2012-06-20 |archive-url=https://web.archive.org/web/20111229114636/http://centerwatch.com/drug-information/fda-approvals/drug-details.aspx?DrugID=105 |archive-date=2011-12-29 }} and was discontinued by its manufacturer in 2012.{{cite web |title=AMAG form 10-K for the fiscal year ended December 31, 2013 |publisher=SEC / Edgar |url=https://www.sec.gov/Archives/edgar/data/792977/000104746914000718/a2218084z10-k.htm}}{{cite web |title=NDA 020410 for GastroMark |publisher=FDA |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020410 |access-date=12 February 2017}}
• 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.{{cite journal |doi=10.3978/j.issn.2223-4292.2011.08.03 |first1=Yi-Xiang J. |last1=Wang |year=2011 |title=Superparamagnetic iron oxide based MRI contrast agents: Current status of clinical application |journal=Quantitative Imaging in Medicine and Surgery |volume=1 |issue=1 |pages=35–40 |pmc=3496483 |pmid=23256052 }} In 2017 GE Healthcare launched a macrocyclic extracellular gadolinium based contrast agent containing gadoteric acid as gadoterate meglumine under the trade name Clariscan.{{cite web |title=Clariscan {{nobr|0.5 mmol / ml}} solution for injection |date=2017-02-22 |df=dmy-all |series=Summary of product characteristics |publisher=GE Healthcare AS |place=Oslo, NO |url=http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1487912585095.pdf |url-status=dead |access-date=2017-02-28 |archive-url=https://web.archive.org/web/20170301092722/http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1487912585095.pdf |archive-date=2017-03-01 }}

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.{{cite journal |last1=Taylor |first1=Robert M. |last2=Huber |first2=Dale L. |last3=Monson |first3=Todd C. |last4=Ali |first4=Abdul-Mehdi S. |last5=Bisoffi |first5=Marco |last6=Sillerud |first6=Laurel O. |year=2011 |title=Multifunctional iron platinum stealth immunomicelles: Targeted detection of human prostate cancer cells using both fluorescence and magnetic resonance imaging |journal=Journal of Nanoparticle Research |volume=13 |issue=10 |pages=4717–4729 |pmid=22121333 |pmc=3223933 |bibcode=2011JNR....13.4717T |doi=10.1007/s11051-011-0439-3}} 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. 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.{{citation needed|date=May 2023}}

Manganese(II) chelates such as Mn-DPDP (mangafodipir) enhance the T₁ signal.{{cite book |first1=Sara |last1=Lacerda|first2=Daouda |last2=Ndiaye|first3=Éva|last3= Tóth |title=Metal Ions in Bio-Imaging Techniques |publisher=Springer |year=2021 |pages=71–99

|chapter=Chapter 3. Manganese Complexes as Contrast Agents for Magnetic Resonance Imaging

|doi=10.1515/9783110685701-009 |s2cid=233682771}} The chelate dissociates in vivo into manganese and DPDP; the manganese is excreted in bile, while DPDP is eliminated via kidney filtration.{{cite journal |last1=Harisinghani |first1=Mukesh G. |last2=Jhaveri |first2=Kartik S. |last3=Weissleder |first3=Ralph |last4=Schima |first4=Wolfgang |last5=Saini |first5=Sanjay |last6=Hahn |first6=Peter F. |last7=Mueller |first7=Peter R. |year=2001 |title=MRI contrast agents for evaluating focal hepatic lesions |journal=Clinical Radiology |volume=56 |issue=9 |pages=714–725 |pmid=11585393 |doi=10.1053/crad.2001.0764}} Mangafodipir has been used in human neuroimaging clinical trials, including for neurodegenerative diseases such as multiple sclerosis.{{cite journal |last1=Sudarshana |first1=D.M. |last2=Nair |first2=G. |last3=Dwyer |first3=J.T. |last4=Steele |first4=S.U. |last5=Suto |first5=D.J. |last6=Wu |first6=T. |last7=Berkowitz |first7=B.A. |last8=Koretsky |first8=A.P |last9=Cortese |first9=I.C.M. |last10=Reich |first10=D.S. |display-authors=6 |date=August 2019 |title=Manganese-enhanced MRI of the brain in healthy volunteers |journal=American Journal of Neuroradiology |volume=40 |issue=8 |pages=1309–1316 |doi=10.3174/ajnr.A6152 |doi-access=free |pmid=31371354 |pmc=6754109}}{{cite journal |last1=Suto |first1=D.J. |last2=Nair |first2=G. |last3=Sudarshana |first3=D.M. |last4=Steel |first4=S.U. |last5=Dwyer |first5=J. |last6=Beck |first6=E.S |last7=Ohayon |first7=J. |last8=Koretsky |first8=A.P. |last9=Cortese |first9=I.C.M. |last10=Reich |first10=D.S. |display-authors=6 |date=August 2020 |title=Manganese-enhanced MRI in patients with multiple sclerosis |journal=American Journal of Neuroradiology |volume=41 |issue=9 |pages=1569–1576 |doi=10.3174/ajnr.A6665 |doi-access=free |pmid=32763897 |pmc=7583091 }} Manganese(II) ions are often used as a contrast agent in animal studies, often called MEMRI (manganese-enhanced MRI).{{cite journal |last1=Koretsky |first1=Alan P. |last2=Silva |first2=Afonso C. |year=2004 |title=Manganese-enhanced magnetic resonance imaging (MEMRI) |journal=NMR in Biomedicine |volume=17 |issue=8 |pages=527–531 |pmid=15617051 |doi=10.1002/nbm.940 |doi-access=free }} Because Mn²⁺ ions can enter cells through calcium transport channels, it has been used for functional brain imaging.{{cite journal |last1=Lin |first1=Yi-Jen |last2=Koretsky |first2=Alan P. |year=1997 |title=Manganese ion enhances T1-weighted MRI during brain activation: An approach to direct imaging of brain function |journal=Magnetic Resonance in Medicine |volume=38 |issue=3 |pages=378–388 |pmid=9339438 |doi=10.1002/mrm.1910380305 |s2cid=25703430 }}

Manganese(III) chelates with porphyrins and phthalocyanines have also been studied.

Unlike the other well-studied iron oxide-based nanoparticles, research on Mn-based nanoparticles is at a relatively early stage.{{cite journal |last1=Zhen |first1=Zipeng |last2=Xie |first2=J. |year=2012 |title=Development of Manganese-Based Nanoparticles as Contrast Probes for Magnetic Resonance Imaging |journal=Theranostics |volume=2 |issue=1 |pages=45–54 |pmid=22272218 |doi=10.7150/thno.3448 |pmc=3263515}}

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.{{cite book |last1 = Lee|first1 = Joseph K.T. |year = 2006 |title = Computed Body Tomography with MRI Correlation |page=87 |publisher = Lippincott Williams & Wilkins |url-access = registration |isbn = 978-0-7817-4526-0 |url = https://archive.org/details/computedbodytomo0000unse_w4n2/page/86/mode/2up |via=Internet Archive}} ({{cite book |title=equivalent link | isbn=9780781745260 |url=https://books.google.com/books?id=3PFZX2r3Hj0C&q=%22manganese%20in%20green%20tea%20and%20blueberry%20juice%22&pg=PA87 |via=Google Books | last1=Lee | first1=Joseph K. T. | date=23 August 2023 | publisher=Lippincott Williams & Wilkins }}

Perflubron, a type of perfluorocarbon, has been used as a gastrointestinal MRI contrast agent for pediatric imaging.{{cite journal |last1=Bisset |first1=G.S. |last2=Emery |first2=K.H. |last3=Meza |first3=M.P. |last4=Rollins |first4=N.K. |last5=Don |first5=S. |last6=Shorr |first6=J.S. |year=1996 |title=Perflubron as a gastrointestinal MR imaging contrast agent in the pediatric population |journal=Pediatric Radiology |volume=26 |issue=6 |pages=409–415 |pmid=8657479 |s2cid=10032242 |doi=10.1007/BF01387316 }} This contrast agent works by reducing the number of hydrogen ions in a body cavity, thus causing it to appear dark in the images.

{{See also|Enzyme-activated MR contrast agents}}

Newer research suggests the possibility of protein based contrast agents, based on the abilities of some amino acids to bind with gadolinium.{{cite journal |doi=10.1002/wnan.1205 |title=Design of a novel class of protein-based magnetic resonance imaging contrast agents for the molecular imaging of cancer biomarkers |year=2013 |last1=Xue |first1=Shenghui |last2=Qiao |first2=Jingjuan |last3=Pu |first3=Fan |last4=Cameron |first4=Mathew |last5=Yang |first5=Jenny J. |journal=Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology |pages=163–179 |pmid=23335551 |volume=5 |issue=2 |pmc=4011496}}{{cite journal |last1=Li |first1=Shunyi |last2=Jiang |first2=Jie |last3=Zou |first3=Jin |last4=Qiao |first4=Jingjuan |last5=Xue |first5=Shenghui |last6=Wei |first6=Lixia |last7=Long |first7=Robert |last8=Wang |first8=Liya |last9=Castiblanco |first9=Adriana |last10=White |first10=Natalie |last11=Ngo |first11=Jen |last12=Mao |first12=Hui |last13=Liu |first13=Zhi-Ren |last14=Yang |first14=Jenny J. |display-authors=6 |year=2012 |title=PEGylation of protein-based MRI contrast agents improves relaxivities and biocompatibilities |journal=Journal of Inorganic Biochemistry |volume=107 |issue=1 |pages=111–118 |pmid=22178673 |pmc=3273044 |doi=10.1016/j.jinorgbio.2011.11.004}}{{cite journal |last1=Xue |first1=Shenghui |last2=Qiao |first2=Jingjuan |last3=Hubbard |first3=Kendra |last4=White |first4=Natalie |last5=Wei |first5=Lixia |last6=Li |first6=Shunyi |last7=Liu |first7=Zhi-Reb |last8=Yang |first8=Jenny J. |last9=Yang |first9=J.J. |display-authors=6 |year=2014 |title=Design of ProCAs (protein-based Gd3+ MRI contrast agents) with high dose efficiency and capability for molecular imaging of cancer biomarkers |journal=Medicinal Research Reviews |volume=34 |issue=5 |pages=1070–1099 |pmid=24615853 |doi=10.1002/med.21313 |s2cid=42641594 }}{{cite journal |last1=Qiao |first1=Jingjuan |last2=Xue |first2=Shenghui |last3=Pu |first3=Fan |last4=White |first4=Natalie |last5=Liu |first5=Zhi-Ren |last6=Yang |first6=Jenny J. |year=2014 |title=Molecular imaging of EGFR/HER2 cancer biomarkers by protein MRI contrast agents |journal=Journal of Biological Inorganic Chemistry |volume=19 |issue=2 |pages=259–270 |pmid=24366655 |doi=10.1007/s00775-013-1076-3 |pmc=3931309 }}

• Lanthanide probes

{{notelist}}

{{reflist|25em}}

{{Commons category|Contrast agents used in magnetic resonance imaging}}

• {{cite web |title=MRI contrast agents |website=magnetic-resonance.org |url=http://www.magnetic-resonance.org/ch/13-01.html }}

{{Contrast media}}

{{DEFAULTSORT:Mri Contrast Agent}}