General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry

Racow, Emily; Kreinbihl, John; Cosby, Alexia G.; Yang, Yi; Pandey, Apurva; Boros, Eszter; Johnson, Christopher J.

doi:10.1021/jacs.9b05874

Cited by 19 publications

(25 citation statements)

References 54 publications

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“…In total, optimised structures and reaction energetics for 23 different Zr 4+ complexes, using 17 different ligands (Figure 11) were calculated. 2,10,38,[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] Structures of the optimised Zr-complexes are presented in Figure 12 and key thermodynamic data are given in Table 2. The ligands chosen were selected based on their reported experimental potential to form stable complexes with 89 Zr 4+…”

Section: Predicting the Absolute And Relative Formation Constants Of Zirconium Complexesmentioning

confidence: 99%

Predicting the Thermodynamic Stability of Zirconium Radiotracers

Holland

2020

Inorg. Chem.

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The thermodynamic stability of a metal−ligand complex, as measured by the formation constant (log), is one of themost important parameters that determines metal ion selectivity and potential applications in, for example, radiopharmaceuticalscience. The stable coordination chemistry of radioactive89Zr4+in an aqueous environment is of paramount importance whendeveloping positronemitting radiotracers based on proteins (usually antibodies) for use with positron emission tomography.Desferrioxamine B (DFO) remains the chelate of choice for clinical applications of89Zr-labeled proteins, but the coordination ofDFO to Zr4+ions is suboptimal. Many alternative ligands have been reported, but the challenges in measuring very high logvalueswith metal ions such as Zr4+that tend to hydrolyze mean that accurate thermodynamic data are scarce. In this work, densityfunctional theory (DFT) calculations were used to predict the reaction energetics for metal ion complexation. Computed values ofpseudoformation constants (log) are correlated with experimental data and showed an excellent linear relationship (R2= 0.97).The model was then used to estimate the absolute and relative formation constants of 23 different Zr4+complexes using a total of 17different ligands, including many of the alternative bifunctional chelates that have been reported recently for use in89Zr4+radiochemistry. In addition, detailed computational studies were performed on the geometric isomerism and hydration state of Zrdesferrioxamine. Collectively, the results offer new insights into Zr4+coordination chemistry that will help guide the synthesis offuture ligands. The computational model developed here is straightforward and reproducible and can be readily applied in the designof other metal coordination compounds.

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Section: Predicting the Absolute And Relative Formation Constants Of Zirconium Complexesmentioning

confidence: 99%

Predicting the Thermodynamic Stability of Zirconium Radiotracers

Holland

2020

Inorg. Chem.

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“…[ZrHL] 2+ [ZrL] + , and [ZrLH –1 ], over the pH range 1–11 . The stability constants and pZr value determined for the Zr(IV)-DFOB system place DFOB among the best Zr(IV) chelators, although the formation of six-coordinate unsaturated complexes (i.e., with the coordination sphere of Zr(IV) completed by two water molecules or hydroxide ligands) and the susceptibility of coordinated water molecules to deprotonation were suggested to be the reason for the in vivo lability of 89 Zr(IV)-DFOB complexes. The thermodynamic stability of Zr(IV)-DFOB complexes is in line with in vivo research ,,, and also with Holland’s recent DFT calculations, indicating that our experimental approach was appropriate.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic Stability and Speciation of Ga(III) and Zr(IV) Complexes with High-Denticity Hydroxamate Chelators

et al. 2021

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Increasing attention has been recently devoted to 89 Zr(IV) and 68 Ga(III) radionuclides, due to their favorable decay characteristics for positron emission tomography (PET). In the present paper, a deep investigation is presented on Ga(III) and Zr(IV) complexes with a series of tri-( H 3 L1 , H 3 L3 , H 3 L4 and desferrioxamine E, DFOE ) and tetrahydroxamate ( H 4 L2 ) ligands. Herein, we describe the rational design and synthesis of two cyclic complexing agents ( H 3 L1 and H 4 L2 ) bearing three and four hydroxamate chelating groups, respectively. The ligand structures allow us to take advantage of the macrocyclic effect; the H 4 L2 chelator contains an additional side amino group available for a possible further conjugation with a biomolecule. The thermodynamic stability of Ga(III) and Zr(IV) complexes in solution has been measured using a combination of potentiometric and pH-dependent UV–vis titrations, on the basis of metal–metal competition. The Zr(IV)- H 4 L2 complex is characterized by one of the highest formation constants reported to date for a tetrahydroxamate zirconium chelate (log β = 45.9, pZr = 37.0), although the complex-stability increase derived from the introduction of the fourth hydroxamate binding unit is lower than that predicted by theoretical calculations. Solution studies on Ga(III) complexes revealed that H 3 L1 and H 4 L2 are stronger chelators in comparison to DFOB. The complex stability obtained with the new ligands is also compared with that previously reported for other hydroxamate ligands. In addition to increasing the library of the thermodynamic stability data of Ga(III) and Zr(IV) complexes, the present work allows new insights into Ga(III) and Zr(IV) coordination chemistry and thermodynamics and broadens the selection of available chelators for 68 Ga(III) and 89 Zr(IV).

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“…[9,10] The only chelator currently used in clinical trials utilizing 89 Zr-labelled Abs is the siderophore desferrioxamine (DFO 1, Figure 1). However, the hexadentate chelator DFO 1 is not ideal for the complexation of zirconium since the metal ion mostly has coordination numbers >6 [11,12]. Therefore, a chelator with a higher denticity, e.g., hepta-or octadentate, would be the more optimal choice.…”

Section: Introductionmentioning

confidence: 99%

Radiolabelling of the octadentate chelators DFO* and oxoDFO* with zirconium-89 and gallium-68

et al. 2020

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In recent years, clinical imaging with zirconium-89 ( 89 Zr)-labelled monoclonal antibodies (Ab) by positron emission tomography (immunoPET) has been gaining significant importance in nuclear medicine for the diagnosis of different types of cancer. For complexation of the radiometal 89 Zr and its attachment to the Ab, chelating agents are required. To date, only the hexadentate chelator desferrioxamine (DFO) is applied in the clinic for this purpose. However, there is increasing preclinical evidence that the [ 89 Zr]Zr-DFO complex is not sufficiently stable and partly releases the radiometal in vivo due to the incomplete coordination sphere of the metal. This leads to unfavourable unspecific uptake of the osteophilic radiometal in bones, hence decreasing the signal-to-noise-ratio and leading to an increased dose to the patient. In the past, several new chelators with denticities >6 have been published, notably the octadentate DFO derivative DFO*. DFO* however shows limited water solubility, wherefore an oxygen containing analogue, termed oxoDFO*, was developed in 2017. However, no data on the suitability of oxoDFO* for radiolabelling with 89 Zr has yet been reported. In this proofof-concept study, we present the first radiolabelling results of the octadentate, water-soluble chelator oxoDFO*, as well as the in vitro stability of the resulting complex [ 89 Zr]Zr-oxoDFO* in comparison to the analogous octadentate, but less water soluble derivative DFO* and the current "standard" chelator DFO. In addition, the suitability of DFO* and oxoDFO* for radiolabeling with the short-lived PET metal gallium-68 is discussed.

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General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry

Cited by 19 publications

References 54 publications

Predicting the Thermodynamic Stability of Zirconium Radiotracers

Predicting the Thermodynamic Stability of Zirconium Radiotracers

Thermodynamic Stability and Speciation of Ga(III) and Zr(IV) Complexes with High-Denticity Hydroxamate Chelators

Radiolabelling of the octadentate chelators DFO* and oxoDFO* with zirconium-89 and gallium-68

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