Contrast agents for MRI: 30+ years and where are we going?

Abstract

Thirty years ago, Schering AG filed the first patent application for a contrast agent for magnetic resonance imaging (MRI) covering the forefather and still the most widely used gadolinium probe: Gd-DTPA or Magnevist. To date, a total of eleven contrast agents have been approved by the US Food and Drug Administration for intravenous use. During that time, coordination chemists have done a great deal to move the field forward. Our understanding of lanthanide chemistry now enables the design of complexes with long rotational correlation times, fast or slow water-exchange rates, high thermodynamic stabilities, and kinetic inertness leading to sensitive and non-toxic contrast agents. Chemists did not stop there. The last few decades have seen the development of novel classes of probes that yield contrast through different mechanisms, such as PARACEST agents. Thirty years since the first patent, chemists are still leading the way. The development of high sensitivity contrast agents for high magnetic fields, safe probes for patients suffering from kidney disorders, and multimodal, targeted, and responsive agents demonstrate that the field of contrast agents for MRI still has much to offer.

Mono-, Bi-, and Trinuclear Bis-Hydrated Mn2+ Complexes as Potential MRI Contrast Agents

“…Similarly to the mX(dpama) 2 4− ligand, the differences between log K 1 H , log K 2 H and log K 3 H of mX(dpama) 3 6− are larger than expected according to the statistical factor. However, the protonation of the carboxylate groups of mX(dpama) 2 4− characterized by Δlog K H = log K 3 H − log K 4 H = 0.8, as well as those of mX(dpama) 3 6− given by Δlog K H = log K 4 H − log K 5 H = 0.6, approaches the behavior expected according to the statistical factor. This is likely related to the longer distances between the involved protonation sites in comparison to the amine nitrogen 2 4− (13.56), and ∑log K i H /3 of tritopic mX(dpama) 3 6− (12.36) indicates that the total basicity of dpama 2− is higher than that of the average basicity of the dpama 2− units in mX(dpama) 2 4− and mX(dpama) 3 6− .…”

“…The first and second protonation constants of mX(dpama) 2 4− are related to the protonation of the amine nitrogen atoms, whereas subsequent protonations of the ligand take place at the carboxylate groups. Similarly, the logK 1 H , logK 2 H , and logK 3 H values of mX-(dpama) 3 6− are also attributed to the protonation of the amine nitrogen atoms, while subsequent protonation processes take place at the carboxylate groups of the picolinate residues.…”

Iron(III) Contrast Agent Candidates for MRI: a Survey of the Structure–Effect Relationship in the Last 15 ­Years of Studies

“…Meanwhile, myriads of gadolinium(III) models will definitely serve as examples to follow. [31,83,84] In this spirit, Hasserodt presented an interesting model of the Fe 2+ system in which the cross-spin, initiated by various stimuli, led to the transformation of a diamagnetic, low-spin complex into a high-spin paramagnet. [85] Such off/on systems have been shown, for instance, to transform their coordination spheres by the action of chemical or enzymatic-reducing agents from 6N to 5N1O, thus leading to a significant signal in the MRI scanner.…”

Amino-phenol complexes of Fe(III) as promising T1 accelerators

“…The quest for new CAs is spreading via various routes: smart CAs, bimodal agents (CT-MRIs), high relaxivity, unique selectivity, etc. (Caravan, 2009;Major and Meade, 2009;Pierre et al, 2014). Higher exploitation of endogenous metals (Mn, Fe) belongs to one of these routes (Schwert et al, 2002) since diseases such as nephrogenic systemic fibrosis (NSF), caused by the gadolinium species in the case of kidney dysfunction (Yerram et al, 2007), and environmental issues (Ku¨mmerer and Helmers, 2000) obscure some of their potential advantages.…”