Structure, Dynamics, and Computational Studies of Lanthanide‐Based Contrast Agents

Peters, Joop A.; Djanashvili, Kristina; Geraldes, Carlos F. G. C.; Platas‐Iglesias, Carlos

doi:10.1002/9781118503652.ch5

Cited by 21 publications

(20 citation statements)

References 487 publications

(574 reference statements)

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“…This shift is purely of contact origin and is, to a first approximation, linearly proportional to q (23,24). This shift is purely of contact origin and is, to a first approximation, linearly proportional to q (23,24).…”

Section: Variation Of Q and R Gdhmentioning

confidence: 86%

“…The value of q can be estimated from the Gd 3+ induced shift of the water 17 O nucleus, provided that the exchange between bound and bulk water is fast on the 17 O NMR time scale. This shift is purely of contact origin and is, to a first approximation, linearly proportional to q (23,24). A widely used alternative method to estimate q values of Gd 3+ complexes is from q values of corresponding Eu 3+ and/or Tb 3+ complexes as determined by their luminescence decay rates in H 2 O and D 2 O (25).…”

Section: Variation Of Q and R Gdhmentioning

confidence: 99%

See 1 more Smart Citation

The reliability of parameters obtained by fitting of ¹H NMRD profiles and ¹⁷O NMR data of potential Gd³⁺‐based MRI contrast agents

Peters

2015

Contrast Media & Molecular

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Synthetic variable temperature (1)H NMRD profiles and (17)O NMR relaxation and shift data were generated with a model based on the Solomon-Bloembergen-Morgan and Freed theories and then fitted simultaneously or individually. The effects of the fitting procedure and of experimental uncertainties on the resulting best-fit parameters were investigated. The most reliable best-fit parameters were obtained when all data were included in a simultaneous fitting procedure. Fitting of only NMRD and/or (17)O NMR data provided considerably less accurate best-fit parameters. Very large deviations from the values of the parameters used for the construction of the datasets were obtained due to the combined effects of uncertainties resulting from the fitting and from the data. For these fittings, the accuracy of the best-fit parameters appeared to be strongly dependent on the magnitude of synthetic parameters applied. For example, the accuracy of τM (C) was low around τM (S) = 10(-8) s. The parameters τV and Δ(2) are strongly correlated in fittings of only (17)O NMR data. Consequently, only the ratio of these parameters can be evaluated in this way. The observations underline the need to reduce the number of adjustable parameters by constraining as many as possible of them at values obtained by independent techniques. The inaccuracies observed in these simulations come in addition to those caused by the inadequacy of the Solomon-Bloembergen-Morgan theory, particularly at low magnetic field strengths.

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Section: Variation Of Q and R Gdhmentioning

confidence: 86%

Section: Variation Of Q and R Gdhmentioning

confidence: 99%

The reliability of parameters obtained by fitting of ¹H NMRD profiles and ¹⁷O NMR data of potential Gd³⁺‐based MRI contrast agents

Peters

2015

Contrast Media & Molecular

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“…Kinetically inert lanthanide(III) complexes have been explored for optical and magnetic bioimaging , and are dominated by octa- and nonadentate chelators made from macrocyclic 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,7-triazacyclononane backbones. , In particular, cyclen with four carboxylate (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA) or carboxamide pendant arms has been studied in great detail. ,,,− The size match between these macrocyclic chelators and the lanthanide(III) ions results in the remarkable inertness of the DOTA-like complexes. ,,,− Because the structure is critical for the performance and properties of the molecule, the solution structure of the lanthanide complexes in use as magnetic resonance imaging (MRI) contrast agents has been described in detail. ,− Further, the structure of DOTA is one of the limiting forms that nine-coordinate complexes can have in solution. The solution to the Thompson problem for a coordination number (CN) of 9 is a tricapped trigonal prism, yet this structure and the capped square antiprism are both found as the limiting geometric structure of lanthanide complexes in the solid state and solution. , The DOTA-like ligands can further adopt a capped twisted square antiprism (cTSAP).…”

Section: Introductionmentioning

confidence: 99%

Including and Declaring Structural Fluctuations in the Study of Lanthanide(III) Coordination Chemistry in Solution

2019

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The physicochemical properties of lanthanide-(III) ions are directly linked to the structure of the surrounding ligands. Rapid ligand exchange prohibits direct structure−property relationships from being formed for simple complexes in solution because the property measured will be an average over several structures. For kinetically inert lanthanide(III) complexes, the simpler speciation may alleviate the problem, yet the archetypical complexes formed by ligands derived from cyclen are known to have at least four different forms in solutioneach with a variation in the crystal field that gives rise to significantly different properties. Slow interchange between forms has been engineered, so that a single complex geometry can be studied, but fast or intermediate interchange between forms is much more commonly observed. The rapid structural fluctuation can report on the changing chemical environment and can be disregarded if a specific property of a lanthanide(III) complex is exploited in an application. However, if we are to understand the chemistry of the lanthanide(III) ions in solution, we must include the structural fluctuation that takes place even in kinetically inert lanthanide(III) complexes in our studies. Here, we have scrutinized the processes that determine the speciation of lanthanide(III) complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA)-like ligands, in particular the processes that enable exchange between forms that have different physicochemical properties, exemplified by the exchange between the diastereomeric capped square-antiprismatic (cSAP) and capped twisted-square-antiprismatic (cTSAP) forms of DOTA-like lanthanide(III) complexes. In the characterization of a kinetically inert f-element complex, understanding the structural fluctuation in the system is critical because a single observed property can arise from a weighted average, from all forms present, or from a single form with a dominating contribution. Further, the experimental condition will influence both the distribution of lanthanide(III) species in solution and the rates of the processes that change the coordination sphere of the lanthanide(III) ions. This is highlighted using data from a series of cyclen-derived ligands with different pendant arms and different denticity. The data were obtained in experiments that take place on different time scales to show that the rate of the process that results in a structural change must be considered against the time of the experiment. We conclude that the structural fluctuations must be taken into account and that they cannot be predicted from the ligand structure. Thus, an estimate of the exchange rates between forms, the relative concentrations of the specific forms, and the effect of the specific structure of each form of the complex must be included in the description of the solution properties of f-element chelates.

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“…In this best-fit procedure, the Gd–H w distance ( r GdH ) was set to 3.1 Å, the distance of the closest approach of the OS water molecules to the gadolinium(III) ion ( a GdH ) was fixed to 4.0 Å, and the values of 1.3, 2.24, and 3.1 (×10 –5 cm 2 s –1 ) were used for the water-solute relative diffusion coefficient ( D ) at 283, 298, and 310 K, respectively. The number of coordinated water molecules ( q ) was fixed to 1, similar to complexes of related DOTA-like ligands . The fit was performed using the following adjustable parameters: the overall molecular tumbling time of the complex (τ R ) and the electronic relaxation parameters Δ 2 (trace of the squared zero-field-splitting, ZFS, tensor) and τ V (correlation time for modulation of the transient ZFS).…”

Section: Resultsmentioning

confidence: 99%

Lanthanide Complexes of DO3A–(Dibenzylamino)methylphosphinate: Effect of Protonation of the Dibenzylamino Group on the Water-Exchange Rate and the Binding of Human Serum Albumin

et al. 2019

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Protonation of a distant, noncoordinated group of metal-based magnetic resonance imaging contrast agents potentially changes their relaxivity. The effect of a positive charge of the drug on the human serum albumin (HSA)–drug interaction remains poorly understood as well. Accordingly, a (dibenzylamino)methylphosphinate derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was efficiently synthesized using pyridine as the solvent for a Mannich-type reaction of tBu3DO3A, formaldehyde, and Bn2NCH2PO2H2 ethyl ester. The ligand protonation and metal ion (Gd3+, Cu2+, and Zn2+) stability constants were similar to those of the parent DOTA, whereas the basicity of the side-chain amino group of the complexes (logK A = 5.8) was 1 order of magnitude lower than that of the free ligand (log K A = 6.8). The presence of one bound water molecule in both deprotonated and protonated forms of the gadolinium(III) complex was deduced from the solid-state X-ray diffraction data [gadolinium(III) and dysprosium(III)], from the square antiprism/twisted square antiprism (SA/TSA) isomer ratio along the lanthanide series, from the fluorescence data of the europium(III) complex, and from the 17O NMR measurements of the dysprosium(III) and gadolinium(III) complexes. In the gadolinium(III) complex with the deprotonated amino group, water exchange is extremely fast (τM = 6 ns at 25 °C), most likely thanks to the high abundance of the TSA isomer and to the presence of a proximate protonable group, which assists the water-exchange process. The interaction between lanthanide(III) complexes and HSA is pH-dependent, and the deprotonated form is bound much more efficaciously (∼13% and ∼70% bound complex at pH = 4 and 7, respectively). The relaxivities of the complex and its HSA adduct are also pH-dependent, and the latter is approximately 2–3 times increased at pH = 4–7. The relaxivity for the supramolecular HSA–complex adduct (r 1 b) is as high as 52 mM–1 s–1 at neutral pH (at 20 MHz and 25 °C). The findings of this study stand as a proof-of-concept, showing the ability to manipulate an albumin–drug interaction, and thus the blood pool residence time of the drug, by introducing a positive charge in a side-chain amino group.

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Structure, Dynamics, and Computational Studies of Lanthanide‐Based Contrast Agents

Cited by 21 publications

References 487 publications

The reliability of parameters obtained by fitting of ¹H NMRD profiles and ¹⁷O NMR data of potential Gd³⁺‐based MRI contrast agents

The reliability of parameters obtained by fitting of ¹H NMRD profiles and ¹⁷O NMR data of potential Gd³⁺‐based MRI contrast agents

Including and Declaring Structural Fluctuations in the Study of Lanthanide(III) Coordination Chemistry in Solution

Lanthanide Complexes of DO3A–(Dibenzylamino)methylphosphinate: Effect of Protonation of the Dibenzylamino Group on the Water-Exchange Rate and the Binding of Human Serum Albumin

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Structure, Dynamics, and Computational Studies of Lanthanide‐Based Contrast Agents

Cited by 21 publications

References 487 publications

The reliability of parameters obtained by fitting of 1H NMRD profiles and 17O NMR data of potential Gd3+‐based MRI contrast agents

The reliability of parameters obtained by fitting of 1H NMRD profiles and 17O NMR data of potential Gd3+‐based MRI contrast agents

Including and Declaring Structural Fluctuations in the Study of Lanthanide(III) Coordination Chemistry in Solution

Lanthanide Complexes of DO3A–(Dibenzylamino)methylphosphinate: Effect of Protonation of the Dibenzylamino Group on the Water-Exchange Rate and the Binding of Human Serum Albumin

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The reliability of parameters obtained by fitting of ¹H NMRD profiles and ¹⁷O NMR data of potential Gd³⁺‐based MRI contrast agents

The reliability of parameters obtained by fitting of ¹H NMRD profiles and ¹⁷O NMR data of potential Gd³⁺‐based MRI contrast agents