Gadolinium(III)‐Based Dual ¹H/¹⁹F Magnetic Resonance Imaging Probes

Abstract

We present two novel octadentate cyclen‐based ligands bearing one (L1) or two (L2) phenylacetamide pendants with two CF3 groups either at positions 3 and 5 (L1) or 4 (L2). The corresponding Gd3+ complexes possess one coordinated water molecule, as confirmed by luminescence lifetime measurements on the EuIII and TbIII analogues. A detailed 1H and 17O relaxometric characterization has revealed the parameters that govern the relaxivities of these complexes. The water‐exchange rate of the mono‐amide derivative GdL1 (kex298=1.52×106 s−1) is faster than that determined for the bis‐amide complex GdL2 (kex298=0.73×106 s−1). 1H and 19F NMR studies have indicated that the complexes are present in solution almost exclusively as the square‐antiprismatic (SAP) isomers. 19F NMR relaxation studies indicated Gd⋅⋅⋅F distances of 7.4±0.1 and 9.1±0.1 Å for GdL1 and GdL2, respectively. Phantom MRI studies revealed the favorable properties of GdL2 as a dual 1H/19F magnetic resonance imaging (MRI) probe, whereas the shorter Gd⋅⋅⋅F distance of GdL1 reduces the signal‐to‐noise ratio due to the very short transverse relaxation time of the 19F NMR signal.

Water exchange in lanthanide complexes for MRI applications. Lessons learned over the last 25 years

“…Again, a notable decrease of the water exchange is observed upon increasing the positive charge of the complex from 𝑘 ex 298 = 1.52 × 10 6 s −1 to 𝑘 ex 298 = 0.73 × 10 6 s −1 . 37 A very important increase in the water exchange rate was also observed upon replacing one of the coordinated water molecules of [Gd(DTTA-Me)(H 2 O) 2 ] − by a fluoride ligand (Table 1). 23 The explanation of these trends is straightforward: an increase in positive charge results in a stronger electrostatic interaction between the metal ion and the oxygen atom of the inner-sphere water molecule.…”

19F MRI Probes for Multimodal Imaging**

“…[80] In this technique, paramagnetic Gadolinium macrocyclic complexes are frequently used as contrast agents (CA) to increase the sensitivity and accuracy of the images. [5] Their action usually produces brighter images by shortening the longitudinal relaxation time of the water protons. They cannot be used in every case due to the potential of serious side effects such Nephrogenic Systemic Fibrosis.…”

“…Reported metal-fluorine distances were in the range 4.5-10 Å. [5,85] Each probe allowed a short transverse relaxation time of the 19 F nuclei and demonstrated a low signal-to-noise ratio in 19 F NMR/MRI. Typically Gd(III) compounds were used but Dy(III), Tb(III) and Yb(III) also displayed favorable 19 F relaxation properties producing good contrast without special acquisition sequences.…”

“…A common functional group in cyclen-derived and similar ligands is the amide link between a pendant arm and the macrocycle. This functional group can find application in 1 H CEST-type imaging in combination with 19 F. CEST imaging is a [5,85,86] Chemistry-A European Journal relatively new and promising MRI approach in which exogenous or endogenous compounds containing exchangeable protons or exchangeable molecules are selectively saturated and, after transferring this saturation, are detected indirectly by the water signal with increased sensitivity. [84] Within this class of contrasts the reported detection limits were 0.05-5 mM for 1 H CEST and 0.05-30 mM for the 19 F modality.…”

“…1 H MRI is one of the most popular imaging techniques in hospitals, offering knowledge that cannot be obtained any other way [80] . In this technique, paramagnetic Gadolinium macrocyclic complexes are frequently used as contrast agents (CA) to increase the sensitivity and accuracy of the images [5] . Their action usually produces brighter images by shortening the longitudinal relaxation time of the water protons.…”