Calix[4]crowns with perfluoroalkylsulfonylcarboxamide functions: a complexation approach for heavy group 2 metal ions

Reissig, Falco; Bauer, David; Al-Ameed, Karrar; Luber, Sandra; Köckerling, Martin; Steinbach, Jörg; Pietzsch, Hans‐Jürgen; Mamat, Constantin

doi:10.1039/d2qi01637k

Cited by 1 publication

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References 67 publications

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“…This property, coupled with its low charge-to-ionic radius ratio (eight-coordinate ionic radius of 1.48 Å), renders its complexes more labile in comparison to those of metal ions with a higher charge density. Efforts directed toward stabilizing the Ra 2+ ion for use in biomedical applications have primarily focused on chelators bearing either the cone-shaped calixarene − or the diaza-18-crown-6 (D18C6) macrocycle; , each of these structural motifs has been shown to effectively accommodate larger metal ions. , Of these chelators, macropa, an 18-membered macrocycle bearing two picolinic acid pendent arms (Chart ), , has shown the most promise to date. Recent studies from the Wilson and Thorek laboratories revealed that macropa can quantitatively bind 223 Ra in aqueous solution under mild conditions, and the resulting complex appeared to be stable in vivo after administration to mice .…”

Section: Introductionmentioning

confidence: 99%

Reining in Radium for Nuclear Medicine: Extra-Large Chelator Development for an Extra-Large Ion

Simms,

Sibley,

Driscoll

et al. 2023

Inorg. Chem.

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Targeted α therapy (TAT) of soft-tissue cancers using the α particle-emitting radionuclide 223 Ra holds great potential because of its favorable nuclear properties, adequate availability, and established clinical use for treating metastatic prostate cancer of the bone. Despite these advantages, the use of 223 Ra has been largely overshadowed by other α emitters due to its challenging chelation chemistry. A key criterion that needs to be met for a radionuclide to be used in TAT is its stable attachment to a targeting vector via a bifunctional chelator. The low charge density of Ra 2+ arising from its large ionic radius weakens its electrostatic binding interactions with chelators, leading to insufficient complex stability in vivo. In this study, we synthesized and evaluated macropa-XL as a novel chelator for 223 Ra. It bears a large 21-crown-7 macrocyclic core and two picolinate pendent groups, which we hypothesized would effectively saturate the large coordination sphere of the Ra 2+ ion. The structural chemistry of macropa-XL was first established with the nonradioactive Ba 2+ ion using X-ray diffraction and X-ray absorption spectroscopy, which revealed the formation of an 11coordinate complex in a rare anti pendent-arm configuration. Subsequently, the stability constant of the [Ra(macropa-XL)] complex was determined via competitive cation exchange with 223 Ra and 224 Ra radiotracers and compared with that of macropa, the current state-of-the-art chelator for Ra 2+ . A moderate log K ML value of 8.12 was measured for [Ra(macropa-XL)], which is approximately 1.5 log K units lower than the stability constant of [Ra(macropa)]. This relative decrease in Ra 2+ complex stability for macropa-XL versus macropa was further probed using density functional theory calculations. Additionally, macropa-XL was radiolabeled with 223 Ra, and the kinetic stability of the resulting complex was evaluated in human serum. Although macropa-XL could effectively bind 223 Ra under mild conditions, the complex appeared to be unstable to transchelation. Collectively, this study sheds additional light on the chelation chemistry of the exotic Ra 2+ ion and contributes to the small, but growing, number of chelator development efforts for 223 Ra-based TAT.

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Section: Introductionmentioning

confidence: 99%

Reining in Radium for Nuclear Medicine: Extra-Large Chelator Development for an Extra-Large Ion

Simms,

Sibley,

Driscoll

et al. 2023

Inorg. Chem.

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Calix[4]crowns with perfluoroalkylsulfonylcarboxamide functions: a complexation approach for heavy group 2 metal ions

Abstract: Heavy alkaline earth metals offer radionuclides which are promising candidates for radiopharmaceutical applications like barium-131 for diagnosis or radium-223/-224 – with similar chemical properties to barium – for targeted alpha-particle...

Cited by 1 publication

References 67 publications

Reining in Radium for Nuclear Medicine: Extra-Large Chelator Development for an Extra-Large Ion

Reining in Radium for Nuclear Medicine: Extra-Large Chelator Development for an Extra-Large Ion

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