A kinetic investigation of the lanthanide DOTA chelates. Stability and rates of formation and of dissociation of a macrocyclic gadolinium(III) polyaza polycarboxylic MRI contrast agent

Wang, Xiangyun; Jin, Tong; Comblin, Vinciane; Lopez-Mut, Antonio; Merciny, E.; Desreux, Jean F.

doi:10.1021/ic00032a034

Cited by 214 publications

(241 citation statements)

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“…13 simplifies to eqn. 14: (14) Fitting k d data collected in the range of 1.0-3.12 M H + ion concentrations to eqn. 14 gave k 2 =9.54±0.18×10 -4 s -1 and K 2 =0.67±0.03 M -1 .…”

Section: Kinetics Of Dissociationmentioning

confidence: 99%

Equilibrium and Formation/Dissociation Kinetics of Some Ln^IIIPCTA Complexes

Tircsó¹,

Sherry

2006

Inorg. Chem.

156

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The protonation constants (K i H ) of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA) and stability constants of complexes formed between this pyridine containing macrocycle and several different metal ions have been determined in 1.0 M KCl, 25°C and compared to previous literature values. The first protonation constant was found to be 0.5-0.6 log units higher than the value reported previously and a total five protonation steps were detected (log K i H = 11.36, 7.35, 3.83, 2.12 and 1.29). The stability constants of complexes formed between PCTA and Mg 2+ , Ca 2+ , Cu 2+ and Zn 2+ were also somewhat higher than those previously reported but this difference could be largely attributed to the higher first protonation constant of the ligand. Stability constants of complexes formed between PCTA and the Ln 3+ series of ions and Y 3+ were determined by using an "out-of-cell" potentiometric method. These values ranged from log K = 18.15 for Ce(PCTA) to log K = 20.63 for Yb(PCTA), increasing along the lanthanide series in proportion to decreasing Ln 3+ cation size. The rates of complex formation for Ce(PCTA), Eu(PCTA), Y(PCTA) and Yb(PCTA) were followed by conventional UV-VIS spectroscopy in the pH range pH=3.5 -4.4. First order rate constants (saturation kinetics) obtained for different ligand / metal ion ratios were consistent with rapid formation of a diprotonated intermediate, Ln(H 2 PCTA) 2+ . The stabilities of the intermediates as determined from the kinetic data were 2.81, 3.12, 2.97 and 2.69 log K units for Ce(H 2 PCTA), Eu(H 2 PCTA), Y(H 2 PCTA) and Yb(H 2 PCTA), respectively. Rearrangement of these intermediates to the fully chelated complexes was the rate determining step and the rate constant (k r ) for this process was found to be inversely proportional to the proton concentration. The formation rates (k OH ) increased with a decrease in lanthanide ion size (9.68×10 7 M -1 s -1 , 1.74×10 8 M -1 s -1 , 1.13×10 8 M -1 s -1 and 1.11×10 9 M -1 s -1 for Ce(PCTA), Eu(PCTA), Y(PCTA) and Yb(PCTA), respectively). These data indicate that the Ln(PCTA) complexes exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid catalyzed dissociation rates (k 1 ) varied with cation from 9.61×10 -4 M -1 s -1 , 5.08×10 -4 M -1 s -1 , 1.07×10 -3 M -1 s -1 and 2.80×10 -4 M -1 s -1 for Ce(PCTA), Eu(PCTA), Y(PCTA) and Yb(PCTA), respectively.

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“…13 simplifies to eqn. 14: (14) Fitting k d data collected in the range of 1.0-3.12 M H + ion concentrations to eqn. 14 gave k 2 =9.54±0.18×10 -4 s -1 and K 2 =0.67±0.03 M -1 .…”

Section: Kinetics Of Dissociationmentioning

confidence: 99%

Equilibrium and Formation/Dissociation Kinetics of Some Ln^IIIPCTA Complexes

Tircsó¹,

Sherry

2006

Inorg. Chem.

156

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“…39 One method used to combat the toxicity of rare earth metals is to encage these lanthanide ions with a chelating agent, thus rendering them relatively inert in the body. 40 Among the more prominent ligands used in gadolinium contrast agents are DTPA, 40,41 HP-DO3A, 42,43 and DOTA. 44 Of these, DOTA is considered to have high thermodynamic stability and kinetic inertness, and as such is an ideal gadolinium chelating ligand for use in in vivo studies.…”

Section: Introductionmentioning

confidence: 99%

Influence of Dy3+ and Tb3+ doping on 13C dynamic nuclear polarization

Niedbalski

Parish

Kiswandhi

et al. 2017

The Journal of Chemical Physics

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Dynamic nuclear polarization (DNP) is a technique that uses a microwave-driven transfer of high spin alignment from electrons to nuclear spins. This is most effective at low temperature and high magnetic field, and with the invention of the dissolution method, the amplified nuclear magnetic resonance (NMR) signals in the frozen state in DNP can be harnessed in the liquid-state at physiologically acceptable temperature for in vitro and in vivo metabolic studies. A current optimization practice in dissolution DNP is to dope the sample with trace amounts of lanthanides such as Gd 3+ or Ho 3+ , which further improves the polarization. While Gd 3+ and Ho 3+ have been optimized for use in dissolution DNP, other lanthanides have not been exhaustively studied for use in 13 C DNP applications. In this work, two additional lanthanides with relatively high magnetic moments, Dy 3+ and Tb 3+ , were extensively optimized and tested as doping additives for 13 C DNP at 3.35 T and 1.2 K. We have found that both of these lanthanides are also beneficial additives, to a varying degree, for 13 C DNP. The optimal concentrations of Dy 3+ (1.5 mM) and Tb 3+ (0.25 mM) for 13 C DNP were found to be less than that of Gd 3+ (2 mM). W-band electron paramagnetic resonance shows that these enhancements due to Dy 3+ and Tb 3+ doping are accompanied by shortening of electron T 1 of trityl OX063 free radical. Furthermore, when dissolution was employed, Tb 3+ -doped samples were found to have similar liquid-state 13 C NMR signal enhancements compared to samples doped with Gd 3+ , and both Tb 3+ and Dy 3+ had a negligible liquid-state nuclear T 1 shortening effect which contrasts with the significant reduction in T 1 when using Gd 3+ . Our results show that Dy 3+ doping and Tb 3+ doping have a beneficial impact on 13 C DNP both in the solid and liquid states, and that Tb 3+ in particular could be used as a potential alternative to Gd 3+ in 13 C dissolution DNP experiments. Published by AIP Publishing.

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“…DOTA and its derivatives can form stable complexes with divalent and trivalent metals and have been used to chelate a wide range of radiometals, including 111 In, 86 Y, 90 Y, 213 Bi, and 225 Ac [96]. Radiolabeled DOTA derivatives possess a greater in vivo stability than DTPA, owing to their kinetic inertness, a quality which makes them very useful in molecular imaging and radio therapy [97,98]. The ability to secure a radioactive payload is vital for the safety of radiolabeled molecules.…”

Section: Macrocyclic Chelatorsmentioning

confidence: 99%

“…In comparison to DTPA, incorporation of the radiolabel to DOTA occurs slower and with a lower yield. This is thought to be due to poorer formation kinetics, owing to DOTA's rigid structure, and competition with trace metals [81,98,99]. Labeling of DOTA is a one step process which can be improved by the use of a 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) or 2-(Nmorpholino)ethanesulfonic acid (MES) buffer [81,100].…”

Section: Macrocyclic Chelatorsmentioning

confidence: 99%

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

et al. 2014

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Owing to their large size proteinaceous drugs offer higher operative information content compared to the small molecules that correspond to the traditional understanding of druglikeness. As a consequence these drugs allow developing patient-specific therapies that provide the means to go beyond the possibilities of current drug therapy. However, the efficacy of these strategies, in particular "personalized medicine", depends on precise information about individual target expression rates. Molecular imaging combines non-invasive imaging methods with tools of molecular and cellular biology and thus bridges current knowledge to the clinical use. Moreover, nuclear medicine techniques provide therapeutic applications with tracers that behave like the diagnostic tracer. The advantages of radioiodination, still the most versatile radiolabeling strategy, and other labeled compounds comprising covalently attached radioisotopes are compared to the use of chelator-protein conjugates that are complexed with metallic radioisotopes. With the techniques using radioactive isotopes as a reporting unit or even the therapeutic principle, care has to be taken to avoid cleavage of the radionuclide from the protein it is linked to. The tracers used in molecular imaging require labeling techniques that provide site specific conjugation and metabolic stability. Appropriate choice of the radionuclide allows tailoring the properties of the labeled protein to the application required. Until the event of positron emission tomography the spectrum of nuclides used to visualize cellular and biochemical processes was largely restricted to iodine isotopes and 99m-technetium. Today, several nuclides such as 18-fluorine, 68-gallium and 86-yttrium have fundamentally extended the possibilities of tracer design and in turn caused the need for the development of chemical methods for their conjugation.

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A kinetic investigation of the lanthanide DOTA chelates. Stability and rates of formation and of dissociation of a macrocyclic gadolinium(III) polyaza polycarboxylic MRI contrast agent

Cited by 214 publications

References 1 publication

Equilibrium and Formation/Dissociation Kinetics of Some Ln^IIIPCTA Complexes

Equilibrium and Formation/Dissociation Kinetics of Some Ln^IIIPCTA Complexes

Influence of Dy3+ and Tb3+ doping on 13C dynamic nuclear polarization

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

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A kinetic investigation of the lanthanide DOTA chelates. Stability and rates of formation and of dissociation of a macrocyclic gadolinium(III) polyaza polycarboxylic MRI contrast agent

Cited by 214 publications

References 1 publication

Equilibrium and Formation/Dissociation Kinetics of Some LnIIIPCTA Complexes

Equilibrium and Formation/Dissociation Kinetics of Some LnIIIPCTA Complexes

Influence of Dy3+ and Tb3+ doping on 13C dynamic nuclear polarization

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

Contact Info

Product

Resources

About

Equilibrium and Formation/Dissociation Kinetics of Some Ln^IIIPCTA Complexes

Equilibrium and Formation/Dissociation Kinetics of Some Ln^IIIPCTA Complexes