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

Caravan, Peter; Esteban‐Gómez, David; Rodríguez-Rodríguez, Aurora; Platas‐Iglesias, Carlos

doi:10.1039/c9dt01948k

“…A key parameter for MRI applications of paramagnetic complexes is undoubtedly a number of directly coordinated water molecules [52]. Although the Mn(II) and Gd(III) complexes of the studied ligands do not show sufficient stability for in vivo applications, determination of hydration of the complex species will shed some light on their molecular structure in solution and will bring potentially useful information for a design of better ligands having a higher denticity (and expected higher stability).…”

Section: Resultsmentioning

confidence: 99%

Coordination Behavior of 1,4-Disubstituted Cyclen Endowed with Phosphonate, Phosphonate Monoethylester, and H-Phosphinate Pendant Arms

Bárta

¹

,

Hermann

²

,

Kotek

³

2019

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Three 1,4,7,10-tetraazacyclododecane-based ligands disubstituted in 1,4-positions with phosphonic acid, phosphonate monoethyl-ester, and H-phosphinic acid pendant arms, 1,4-H4do2p, 1,4-H2do2pOEt, and 1,4-H2Bn2do2pH, were synthesized and their coordination to selected metal ions, Mg(II), Ca(II), Mn(II), Zn(II), Cu(II), Eu(III), Gd(III), and Tb(III), was investigated. The solid-state structure of the phosphonate ligand, 1,4-H4do2p, was determined by single-crystal X-ray diffraction. Protonation constants of the ligands and stability constants of their complexes were obtained by potentiometry, and their values are comparable to those of previously studied analogous 1,7-disubstitued cyclen derivatives. The Gd(III) complex of 1,4-H4do2p is ~1 order of magnitude more stable than the Gd(III) complex of the 1,7-analogue, probably due to the disubstituted ethylenediamine-like structural motif in 1,4-H4do2p enabling more efficient wrapping of the metal ion. Stability of Gd(III)–1,4-H2do2pOEt and Gd(III)–H2Bn2do2pH complexes is low and the constants cannot be determined due to precipitation of the metal hydroxide. Protonations of the Cu(II), Zn(II), and Gd(III) complexes probably takes place on the coordinated phosphonate groups. Complexes of Mn(II) and alkali-earth metal ions are significantly less stable and are not formed in acidic solutions. Potential presence of water molecule(s) in the coordination spheres of the Mn(II) and Ln(III) complexes was studied by variable-temperature NMR experiments. The Mn(II) complexes of the ligands are not hydrated. The Gd(III)–1,4-H4do2p complex undergoes hydration equilibrium between mono- and bis-hydrated species. Presence of two-species equilibrium was confirmed by UV-Vis spectroscopy of the Eu(III)–1,4-H4do2p complex and hydration states were also determined by luminescence measurements of the Eu(III)/Tb(III)–1,4-H4do2p complexes.

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“…The r1p values for the two magnetic field strengths were found to be 4.46 (20 MHz An important parameter that affects the relaxivity of Gd(III) chelates is the exchange rate of the coordinated water molecule(s). The water exchange rates determined for Gd(III) complexes were found to cover a broad range of four orders of magnitude, 48 with the faster exchange rate corresponding to the aquated ion [Gd(H2O)8] 3+ (kex 298 = 83010 6 s -1 ). 49 The lowest kex 298 values were reported for dota-tetraamide derivatives (0.110 6 s -1 ).…”

Section: =mentioning

confidence: 99%

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation

Nizou¹,

Molnár²,

Hamon³

et al. 2020

Preprint

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We report the synthesis of two pyclen-based regioisomer ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca1(15),11,13-triene) functionalized with picolinic acid pendant arms either at positions 3,9-pc2pa (L5) or 3,6-pc2pa (L6) of the macrocyclic fragment. The ligands were prepared by regiospecific protection of one of the amine nitrogen atom of the macrocycle using Boc and Alloc protecting groups, respectively. The X-ray structure of the Gd(III) complex of L5 contains trinuclear [(GdL5)3(H2O)3] 3+ entities in which the monomeric units are joined by 2- 1 : 1 carboxylate groups. However, the 1H and 89Y NMR spectra of its Y(III) analogue support the formation of monomeric complexes in solution. The Tb(III) complexes are highly luminescent, with emission quantum yields of up to 50% for [TbL5] + . The luminescence lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule coordinated to the metal ion, as also evidenced by the 1H relaxivities measured for the Gd(III) analogues. The Gd(III) complexes present very different exchange rates of the coordinated water molecule (kex 298 = 87.1 and 1.06 106 s -1 for [GdL5] + and [GdL6] + , respectively). The very high water exchange rate of [GdL5] + is associated to the steric hindrance originated by the coordination of the ligand around the water binding site, which favors a dissociatively activated water exchange process. The Gd(III) complexes present rather high thermodynamic stabilities (logKGdL = 20.47 and 19.77 for [GdL5] + and [GdL6] + , respectively). Furthermore, these complexes are remarkably inert with respect to their acid-assisted dissociation, in particular the complex of L5.

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“…An important parameter that affects the relaxivity of Gd(III) chelates is the exchange rate of the coordinated water molecule(s). The water exchange rates determined for Gd(III) complexes were found to cover a broad range of four orders of magnitude, 48 with the faster exchange rate corresponding to the aquated ion [Gd(H2O)8] 3+ (kex 298 = 83010 6 s -1 ). 49 The lowest kex 298 values were reported for dota-tetraamide derivatives (0.110 6 s -1 ).…”

Section: 𝐷 =mentioning

confidence: 99%

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation

Nizou¹,

Molnár²,

Hamon³

et al. 2020

Preprint

Self Cite

0

View full text Add to dashboard Cite

We report the synthesis of two pyclen-based regioisomer ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca1(15),11,13-triene) functionalized with picolinic acid pendant arms either at positions 3,9-pc2pa (L5) or 3,6-pc2pa (L6) of the macrocyclic fragment. The ligands were prepared by regiospecific protection of one of the amine nitrogen atom of the macrocycle using Boc and Alloc protecting groups, respectively. The X-ray structure of the Gd(III) complex of L5 contains trinuclear [(GdL5)3(H2O)3] 3+ entities in which the monomeric units are joined by 2- 1 : 1 carboxylate groups. However, the 1H and 89Y NMR spectra of its Y(III) analogue support the formation of monomeric complexes in solution. The Tb(III) complexes are highly luminescent, with emission quantum yields of up to 50% for [TbL5] + . The luminescence lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule coordinated to the metal ion, as also evidenced by the 1H relaxivities measured for the Gd(III) analogues. The Gd(III) complexes present very different exchange rates of the coordinated water molecule (kex 298 = 87.1 and 1.06 106 s -1 for [GdL5] + and [GdL6] + , respectively). The very high water exchange rate of [GdL5] + is associated to the steric hindrance originated by the coordination of the ligand around the water binding site, which favors a dissociatively activated water exchange process. The Gd(III) complexes present rather high thermodynamic stabilities (logKGdL = 20.47 and 19.77 for [GdL5] + and [GdL6] + , respectively). Furthermore, these complexes are remarkably inert with respect to their acid-assisted dissociation, in particular the complex of L5.

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

Abstract: Coordination chemistry offers convenient strategies to modulate the exchange of coordinated water molecules in lanthanide-based contrast agents.

Cited by 46 publications

References 183 publications

Coordination Behavior of 1,4-Disubstituted Cyclen Endowed with Phosphonate, Phosphonate Monoethylester, and H-Phosphinate Pendant Arms

Coordination Behavior of 1,4-Disubstituted Cyclen Endowed with Phosphonate, Phosphonate Monoethylester, and H-Phosphinate Pendant Arms

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation

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