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Metal Coordination Properties of a Chromophoric Desferrioxamine (DFO) Derivative: Insight on the Coordination Stoichiometry and Thermodynamic Stability of Zr⁴⁺ Complexes.

ABSTRACT: Desferrioxamine (DFO) is the current "gold standard" chelator for ⁸⁹Zr⁴⁺, which is used to label monoclonal antibodies for applications in immunopositron emission tomography. Recently, controversial data have been reported regarding the speciation and the stability of the complexes formed by DFO with Zr⁴⁺ in solution. To shed some light on this point, we studied the coordination properties in solution ofa chromophoric DFO derivative bearing a substituted pyrimidine residue (DFO-Pm) toward several metal ions (Zr⁴⁺, Cu²⁺, Zn²⁺, Mg²⁺, Ca²⁺, Na⁺, K⁺). Potentiometric titrations showed that DFO-Pm and pristine DFO form complexes with very similar stoichiometry and stability. DFO-Pm, which can consequently be taken as a model system for DFO, provides a photochemical response to metal coordination that can be used to further define the complexes formed. In the critical case of Zr⁴⁺, spectrophotometric measurements allowed the verification of the formation of 1:1 and 2:3 complexes that, together with 2:2 complexes form the coordination model that was obtained through the use of our potentiometric measurements. Additionally, mass spectrometry measurements verified the formation of 1:1 and 2:3 complexes and showed that 1:2 species can be easily generated through the fragmentation of the 2:3 species. In conclusion, the results obtained with DFO-Pm validate the complexation model of Zr⁴⁺/DFO composed of 1:1, 2:2, and 2:3 metal-to-ligand complexes. Convergences and conflicts with other works are addressed.

SUBMITTER: Savastano M

PROVIDER: S-EPMC8746621 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Herein we report a new high-denticity chelator based on the iron siderophore desferrioxamine (DFO). Our new chelator-DFO2-is acyclic and was designed and synthesized with the purpose of improving the coordination chemistry and radiolabeling performance with radioactive zirconium-89. The radionuclide zirconium-89 ([89Zr]Zr4+) has found wide use for positron emission tomography (PET) imaging when it is coupled with proteins, antibodies, and nanoparticles. DFO2 has a potential coordination number of 12, which uniquely positions this chelator for binding large, high-valent, and oxophilic metal ions. Following synthesis of the DFO2 chelator and the [natZr]Zr-(DFO2) complex we performed density functional theory calculations to study its coordination sphere, followed by zirconium-89 radiolabeling experiments for comparisons with the "gold standard" chelator DFO. DFO (CN 6) can coordinate with zirconium in a hexadentate fashion, leaving two open coordination sites where water is thought to coordinate (total CN 8). DFO2 (potential CN 12, dodecadentate) can saturate the coordination sphere of zirconium with four hydroxamate groups (CN 8), with no room left for water to directly coordinate, and only binds a single atom of zirconium per chelate. Following quantitative radiolabeling with zirconium-89, the preformed [89Zr]Zr-(DFO) and [89Zr]Zr-(DFO2) radiometal-chelate complexes were subjected to a battery of in vitro stability challenges, including human blood serum, apo-transferrin, serum albumin, iron, hydroxyapatite, and EDTA. One objective of these stability challenges was to determine if the increased denticity of DFO2 over that of DFO imparted improved complex stability, and another was to determine which of these assays is most relevant to perform with future chelators. In all of the assays DFO2 showed superior stability with zirconium-89, except for the iron challenge, where both DFO2 and DFO were identical. Substantial differences in stability were observed for human blood serum using a precipitation method of analysis, apo-transferrin, hydroxyapatite, and EDTA challenges. These results suggest that DFO2 is a promising next-generation scaffold for zirconium-89 chelators and holds promise for radiochemistry with even larger radionuclides, which we anticipate will expand the utility of DFO2 into theranostic applications.

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Metal Coordination Properties of a Chromophoric Desferrioxamine (DFO) Derivative: Insight on the Coordination Stoichiometry and Thermodynamic Stability of Zr⁴⁺ Complexes.

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Metal Coordination Properties of a Chromophoric Desferrioxamine (DFO) Derivative: Insight on the Coordination Stoichiometry and Thermodynamic Stability of Zr4+ Complexes.

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Metal Coordination Properties of a Chromophoric Desferrioxamine (DFO) Derivative: Insight on the Coordination Stoichiometry and Thermodynamic Stability of Zr⁴⁺ Complexes.