Evaluation of H2CHXdedpa, H2dedpa- and H2CHXdedpa-N,N′-propyl-2-NI ligands for 64Cu(<scp>ii</scp>) radiopharmaceuticals

Ramogida, Caterina F.; Boros, Eszter; Patrick, Brian O.; Zeisler, Stefan; Kumlin, Joel; Adam, Michael J.; Schaffer, Paul; Orvig, Chris

doi:10.1039/c6dt00932h

Cited by 15 publications

(14 citation statements)

References 38 publications

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“…This asymmetry is more similar to the rigid [Cu( CHX hox)] structure and could be due to the presence of the rigid pyridine units, although they are not involved in binding. The preference for the [Cu(pyhox)] structure to coordinate the backbone N en as opposed to the pyridine N py likely arises from the slight Jahn–Teller distortion associated with the bonds N en 2-Cu (2.361 Å) and O ox 1-Cu (2.2223 Å), similar to previously characterized chelators for Cu 2+ with comparable coordination spheres. , …”

Section: Results and Discussionsupporting

confidence: 72%

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H₂pyhox – Octadentate Bis(pyridyloxine)

et al. 2021

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A new versatile chelating ligand for intermediate size and softness radiometals [ 64 Cu]Cu 2+ and [ 111 In]In 3+ , H 2 pyhox, was synthesized by introducing pyridine as a new donor moiety to complement 8-hydroxyquinoline on an ethylenediamine backbone. The combination of pyridine and oxine as donor sets was explored through structural analysis, and crystals of the three metal complexes with Cu 2+ , La 3+ , and In 3+ demonstrate how the ligand adapts to accommodate metal ions of different sizes and charge. Exhaustive in-batch UV solution studies characterized the protonation constants of the free ligand as well as the formation constants of the metal complexes with Cu 2+ , In 3+ , and La 3+ . Preliminary concentration-dependent radiolabeling studies with [ 111 In]In 3+ and [ 64 Cu]Cu 2+ show the robustness of H 2 pyhox to successfully coordinate both radiometals under mild conditions (<15 min, room temperature, pH 6). H 2 pyhox is the first oxinate ligand to successfully radiolabel [ 225 Ac]Ac 3+ , albeit only at high concentrations (0.1−1 mM) with gentle heating to 37 °C. Whole serum, protein, and ligand challenge assays further demonstrate the kinetic inertness of the [ 111 In]In 3+ and [ 64 Cu]Cu 2+ radiometalligand complexes, confirming H 2 pyhox to be a promising versatile radiopharmaceutical chelator.

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Section: Results and Discussionsupporting

confidence: 72%

“…Synthesis of H 2 pyhox (1) 2+ with comparable coordination spheres. 35,36 In 3+ is a medium sized metal ion (0.80 Å) 33 with a preference for CN 6−8. Although pyhox 2− is a potentially octadentate chelator, In 3+ prefers hexacoordination over octacoordination with H 2 pyhox.…”

Section: ■ Introductionmentioning

confidence: 99%

H₂pyhox – Octadentate Bis(pyridyloxine)

et al. 2021

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“…Faster complexation is observed with N-phosphonic acid analogues, although heating is still necessary for the moment. 49,50,51,52 New linear systems such as H 2 DEDPA and H2AZAPA 53,54 as well as other type of macrocyclic ligands and cages (DiamSar 55,56,57 and its derivatives) offer good radiolabelling conditions at room temperature (Chart 2) and for some of them, a high degree of kinetic inertness. Bispidine derivatives (L 4 and L 5 , Chart 2) also form particularly stable Cu (II) complexes in vitro and in vivo.…”

Section: Chart 2 Structure Of Other Ligands Discussed In This Workmentioning

confidence: 99%

A Bispidol Chelator with a Phosphonate Pendant Arm: Synthesis, Cu(II) Complexation, and ⁶⁴Cu Labeling

et al. 2017

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Here we present the synthesis and characterization of a new bispidine (3,7-diazabicyclo[3.3.1]nonane) ligand with N-methanephosphonate substituents (L). Its physicochemical properties in water, as well as those of the corresponding Cu(II) and Zn(II) complexes, have been evaluated by using UV-visible absorption spectroscopy, potentiometry, H andP NMR, and cyclic voltammetry. Radiolabeling experiments with Cu have been carried out, showing excellent radiolabeling properties. Quantitative complexation was achieved within 60 min under stoichiometric conditions, at room temperature and in the nanomolar concentration range. It was also demonstrated that the complexation occurred below pH 2. Properties have been compared to those of the analogue bispidol bearing a N-methanecarboxylate substituent (L). Although both systems meet the required criteria to be used as new chelator for Cu in terms of the kinetics of formation, thermodynamic stability, selectivity for Cu(II), and kinetic inertness regarding redox- or acid-assisted decomplexation processes, substitution of the carboxylic acid function by the phosphonic moiety is responsible for a significant increase in the thermodynamic stability of the Cu(II) complex (+2 log units for pCu) and also leads to an increase in the radiochemical yields withCu which is quantitative for L.

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“…Cu + possesses markedly different coordination preferences compared to Cu 2+ and is much more labile to ligand exchange. Therefore, premature dissociation and release of 64/67 Cu can occur. − As such, it is important for a BFC selected for 64/67 Cu to be able to firmly complex both Cu 2+ and Cu + or to stabilize Cu 2+ to prevent reduction. ,− …”

Section: Introductionmentioning

confidence: 99%

Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in ^64/67Cu Radiopharmaceuticals

et al. 2021

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The Cu 2+ complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV–vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV–vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag + –Cu 2+ competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu 2+ complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu 2+ complexes in aqueous solution were investigated by UV–vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO 3 )]·NO 3 and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu 2+ to Cu + on the CV time scale. The Cu + complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu 2+ and Cu + complexes can represent a key parameter for avoiding in vivo demetalation after bioinduced reduction to Cu + , often observed for other well-known chelators that can stabilize only Cu 2+ .

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Evaluation of H₂CHXdedpa, H₂dedpa- and H₂CHXdedpa-N,N′-propyl-2-NI ligands for ⁶⁴Cu(ii) radiopharmaceuticals

Cited by 15 publications

References 38 publications

H₂pyhox – Octadentate Bis(pyridyloxine)

H₂pyhox – Octadentate Bis(pyridyloxine)

A Bispidol Chelator with a Phosphonate Pendant Arm: Synthesis, Cu(II) Complexation, and ⁶⁴Cu Labeling

Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in ^64/67Cu Radiopharmaceuticals

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Evaluation of H2CHXdedpa, H2dedpa- and H2CHXdedpa-N,N′-propyl-2-NI ligands for 64Cu(ii) radiopharmaceuticals

Cited by 15 publications

References 38 publications

H2pyhox – Octadentate Bis(pyridyloxine)

H2pyhox – Octadentate Bis(pyridyloxine)

A Bispidol Chelator with a Phosphonate Pendant Arm: Synthesis, Cu(II) Complexation, and 64Cu Labeling

Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in 64/67Cu Radiopharmaceuticals

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Evaluation of H₂CHXdedpa, H₂dedpa- and H₂CHXdedpa-N,N′-propyl-2-NI ligands for ⁶⁴Cu(ii) radiopharmaceuticals

H₂pyhox – Octadentate Bis(pyridyloxine)

H₂pyhox – Octadentate Bis(pyridyloxine)

A Bispidol Chelator with a Phosphonate Pendant Arm: Synthesis, Cu(II) Complexation, and ⁶⁴Cu Labeling

Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in ^64/67Cu Radiopharmaceuticals