A Manganese-based Alternative to Gadolinium: Contrast-enhanced MR Angiography, Excretion, Pharmacokinetics, and Metabolism

Gale, Eric M.; Wey, Hsiao‐Ying; Ramsay, Ian; Yen, Yi‐Fen; Sosnovik, David E.; Caravan, Peter

doi:10.1148/radiol.2017170977

Cited by 103 publications

(118 citation statements)

References 29 publications

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“…These two metal ions are the most promising for the development of Gd-free MRI contrast agents, based on their magnetic properties and their roles as trace elements in human biology. There has been much progress in the development of Mn(II) complexes as MRI probes [9][10][11][12][13]. However, despite the prominent role of iron in human biology, there are significantly fewer studies on Fe(III)-based contrast agents [14][15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups

et al. 2020

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Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH2), are compared. Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r1 relaxivity of the Fe(L1)(OH2) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 °C in buffered solutions. However, variable-temperature 17O-NMR experiments show that the inner-sphere water of Fe(L1)(OH2) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH2) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH2) for development as an extracellular fluid contrast agent.

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Section: Introductionmentioning

confidence: 99%

Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups

et al. 2020

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“…It has recently been observed in humans and preclinical models that low levels of Gd can be detected in tissue, particularly in the central nervous system following administration of multiple doses of gadoliniumbased contrast agents (GBCA) [2][3][4]. While adverse health outcomes have not been associated with this retention, the observation has revived interest in MRI active chelates of biotic metals; candidates include manganese [5,6] and iron [7][8][9][10]. Manganese [11] and iron [12] are essential to living organisms, which have consequently developed dedicated biological pathways for achieving homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Fe-HBED Analogs: A Promising Class of Iron-Chelate Contrast Agents for Magnetic Resonance Imaging

Bales

Grimmond

Johnson

et al. 2019

Contrast Media & Molecular Imaging

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Contrast-enhanced magnetic resonance imaging is an essential tool for disease diagnosis and management; all marketed clinical magnetic resonance imaging (MRI) contrast agents (CAs) are gadolinium (Gd) chelates and most are extracellular fluid (ECF) agents. After intravenous injection, these agents rapidly distribute to the extracellular space and are also characterized by low serum protein binding and predominant renal clearance. Gd is an abiotic element with no biological recycling processes; low levels of Gd have been detected in the central nervous system and bone long after administration. These observations have prompted interest in the development of new MRI contrast agents based on biotic elements such as iron (Fe); Fe-HBED (HBED = N,N′-bis(2-hydroxyphenyl)ethylenediamine-N,N′-diacetic acid), a coordinatively saturated iron chelate, is an attractive MRI CA platform suitable for modification to adjust relaxivity and biodistribution. Compared to the parent Fe-HBED, the Fe-HBED analogs reported here have lower serum protein binding and higher relaxivity as well as lower relative liver enhancement in mice, comparable to that of a representative gadolinium-based contrast agent (GBCA). Fe-HBED analogs are therefore a promising class of non-Gd ECF MRI CA.

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“…The best compromise between sufficient stability and contrast enhancement described so far was achieved with chelators on the basis of the 1,2‐trans‐cyclohexyldiaminocarboxylate (CDTA 4 ) scaffold, for example, PyC3A 5 (Figure with structure 4 ‐ 6 ) . Gale et al reported in 2015 that the Mn (II) complex of PyC3A proved to be of sufficient thermodynamic stability (logK MnL = 14.14) and suitable for contrast‐enhanced MR angiography . This successful proof‐of‐concept study represents an important step towards the development of new alternatives of Gd‐based MR contrast agents.…”

Section: Manganese‐52g In Preclinical Researchmentioning

confidence: 92%

“…Since a water molecule as an additional ligand inside the coordination sphere of the metal is required for contrast enhancement, Mn (II) complexes with hexa‐ or lower dentate ligand systems and at least one inner sphere water molecule are potential candidates for MRI contrast agents . The tendency of the chelator DOTA 1 to form octadentate complexes with manganese of excellent stability (see above) has its downside in this context: Because of the lack of an inner sphere water molecule in [ nat Mn (DOTA)], there is no MR contrast (Table ).…”

Section: Manganese‐52g In Preclinical Researchmentioning

confidence: 99%

Manganese in PET imaging: Opportunities and challenges

Brandt

Cardinale

Rausch

et al. 2019

Labelled Comp Radiopharmac

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Several radionuclides of the transition metal manganese are known and accessible. Three of them, 51Mn, 52mMn, and 52gMn, are positron emitters that are potentially interesting for positron emission tomography (PET) applications and, thus, have caught the interest of the radiochemical/radiopharmaceutical and nuclear medicine communities. This mini‐review provides an overview of the production routes and physical properties of these radionuclides. For medical imaging, the focus is on the longer‐living 52gMn and its application for the radiolabelling of molecules and other entities exhibiting long biological half‐lives, the imaging of manganese‐dependent biological processes, and the development of bimodal PET/magnetic resonance imaging (MRI) probes in combination with paramagnetic natMn as a contrast agent.

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A Manganese-based Alternative to Gadolinium: Contrast-enhanced MR Angiography, Excretion, Pharmacokinetics, and Metabolism

Cited by 103 publications

References 29 publications

Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups

Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups

Fe-HBED Analogs: A Promising Class of Iron-Chelate Contrast Agents for Magnetic Resonance Imaging

Manganese in PET imaging: Opportunities and challenges

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