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

Abstract

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.

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

“…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].…”

Iron (III)-Quercetin Complex: Synthesis, Physicochemical Characterization, and MRI Cell Tracking toward Potential Applications in Regenerative Medicine

“…However, the oxidative state of iron (II) without the magnetic property did not affect T1 relaxation. Numerous iron (III) complexes with small molecules beyond quercetin were representative of a T1-positive contrast agent, such as + Fe-DTPA, Fe-tCDTA, Fe-HBED, and Fe-3FCAT 3 [ 15 – 17 ]. In general, in the experimental settings for determining the T1 relaxivity of the contrast agent, solvents such as water are most often used, even though they do not mimic the relevant physiological conditions; a physiological medium of human plasma was also used.…”

“…A reduction in the r1 value of the iron (III)-water complex in plasma might occur as a result of two specific factors: (1) the water-protein ligand exchanges known as ligand effects and (2) the reduction of iron (III) under a high spin to iron (II) oxidation state, identified as a low spin by plasma proteins. Three mechanisms are considered to contribute to the relaxivity of IronQ: (1) inner-sphere relaxation through iron (III)-coordinated water molecule exchanges with other water molecules, (2) second-sphere relaxation where hydrogen bound water molecules are present in the second coordination sphere or an exchangeable hydrogen atom (such as O–H and N–H) between water and plasma proteins that undergoes relaxation and exchange, and (3) outer-sphere relaxation, where water molecules can be diffused close to the IronQ and can also be relaxed [ 17 , 64 ]. The T2 relaxivity of IronQ was not evaluated in terms of its value because this complex was not involved with the spin-spin relaxation process.…”

“…Currently, iron (III) is an organometallic ion with biocompatibility, which is well known in terms of its biochemistry and homeostasis in living cells and organisms [ 14 ]. It has been developed for both T1-positive [ 10 , 15 – 17 ] and T2-negative [ 18 , 19 ] contrast enhancements. Iron (III) is a d-block transition metal, with five unpaired electrons favoring the formation of six-coordination bonding to the bidentate or tridentate ligands in an octahedral molecular geometrical arrangement [ 20 ].…”

Role of gadolinium-based contrast agents in neurological disorders

“…Studies indicate that both of these challenges can be addressed with a proper chelate structure design. Recent research by Bales et al has proposed using the Fe-HBED analogues which, compared to the parent Fe-HBED, have lower serum protein binding and higher relaxivity than do a representative GBCA [96].…”