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Rational Design, Synthesis and Preliminary Evaluation of Novel Fusarinine C-Based Chelators for Radiolabeling with Zirconium-89.

ABSTRACT: Fusarinine C (FSC) has recently been shown to be a promising and novel chelator for ⁸⁹Zr. Here, FSC has been further derivatized to optimize the complexation properties of FSC-based chelators for ⁸⁹Zr-labeling by introducing additional carboxylic groups. These were expected to improve the stability of ⁸⁹Zr-complexes by saturating the 8-coordination sphere of [⁸⁹Zr] Zr⁴⁺, and also to introduce functionalities suitable for conjugation to targeting vectors such as monoclonal antibodies. For proof of concept, succinic acid derivatization at the amine groups of FSC was carried out, resulting in FSC(succ)? and FSC(succ)?. FSC(succ)? was further derivatized to FSC(succ)? AA by reacting with acetic anhydride (AA). The Zr⁴⁺ complexation properties of these chelators were studied by reacting with ZrCl?. Partition coefficient, protein binding, serum stability, acid dissociation, and transchelation studies of ⁸⁹Zr-complexes were carried out in vitro and the results were compared with those for ⁸⁹Zr-desferrioxamine B ([⁸⁹Zr]Zr-DFO) and ⁸⁹Zr-triacetylfusarinine C ([⁸⁹Zr]Zr-TAFC). The in vivo properties of [⁸⁹Zr]Zr-FSC(succ)? were further compared with [⁸⁹Zr]Zr-TAFC in BALB/c mice using micro-positron emission tomography/computer tomography (microPET/CT) imaging. Fusarinine C (succ)?AA and FSC(succ)? were synthesized with satisfactory yields. Complexation with ZrCl? was achieved using a simple strategy resulting in high-purity Zr-FSC(succ)?AA and Zr-FSC(succ)? with 1:1 stoichiometry. Distribution coefficients of ⁸⁹Zr-complexes revealed increased hydrophilic character compared to [⁸⁹Zr]Zr-TAFC. All radioligands showed high stability in phosphate buffered saline (PBS) and human serum and low protein-bound activity over a period of seven days. Acid dissociation and transchelation studies exhibited a range of in vitro stabilities following the order: [⁸⁹Zr]Zr-FSC(succ)? > [⁸⁹Zr]Zr-TAFC > [⁸⁹Zr]Zr-FSC(succ)?AA >> [⁸⁹Zr]Zr-DFO. Biodistribution studies of [⁸⁹Zr]Zr-FSC(succ)? revealed a slower excretion pattern compared to [⁸⁹Zr]Zr-TAFC. In conclusion, [⁸⁹Zr]Zr-FSC(succ)? showed the best stability and inertness. The promising results obtained with [⁸⁹Zr]Zr-FSC(succ)?AA highlight the potential of FSC(succ)? as a monovalent chelator for conjugation to targeted biomolecules, in particular, monoclonal antibodies.

SUBMITTER: Zhai C

PROVIDER: S-EPMC6468543 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Rational Design, Synthesis and Preliminary Evaluation of Novel Fusarinine C-Based Chelators for Radiolabeling with Zirconium-89.

Zhai Chuangyan C He Shanzhen S Ye Yunjie Y Rangger Christine C Kaeopookum Piriya P Summer Dominik D Haas Hubertus H Kremser Leopold L Lindner Herbert H Foster Julie J Sosabowski Jane J Decristoforo Clemens C

Biomolecules 20190306 3

Fusarinine C (FSC) has recently been shown to be a promising and novel chelator for 89Zr. Here, FSC has been further derivatized to optimize the complexation properties of FSC-based chelators for 89Zr-labeling by introducing additional carboxylic groups. These were expected to improve the stability of 89Zr-complexes by saturating the 8-coordination sphere of [89Zr] Zr4+, and also to introduce functionalities suitable for conjugation to targe ...[more]

PMID: 30845658

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Project description:Metals of interest for biomedical applications often need to be complexed and associated in a stable manner with a targeting agent before use. Whereas the fundamentals of most transition-metal complexation processes have been thoroughly studied, the complexation of Zr(IV) has been somewhat neglected. This metal has received growing attention in recent years, especially in nuclear medicine, with the use of (89) Zr, which a ?(+) -emitter with near ideal characteristics for cancer imaging. However, the best chelating agent known for this radionuclide is the trishydroxamate desferrioxamine?B (DFB), the Zr(IV) complex of which exhibits suboptimal stability, resulting in the progressive release of (89) Zr in vivo. Based on a recent report demonstrating the higher thermodynamic stability of the tetrahydroxamate complexes of Zr(IV) compared with the trishydroxamate complexes analogues to DFB, we designed a series of tetrahydroxamic acids of varying geometries for improved complexation of this metal. Three macrocycles differing in their cavity size (28 to 36-membered rings) were synthesized by using a ring-closing metathesis strategy, as well as their acyclic analogues. A solution study with (89) Zr showed the complexation to be more effective with increasing cavity size. Evaluation of the kinetic inertness of these new complexes in ethylenediaminetetraacetic acid (EDTA) solution showed significantly improved stabilities of the larger chelates compared with (89) Zr-DFB, whereas the smaller complexes suffered from insufficient stabilities. These results were rationalized by a quantum chemical study. The lower stability of the smaller chelates was attributed to ring strain, whereas the better stability of the larger cyclic complexes was explained by the macrocyclic effect and by the structural rigidity. Overall, these new chelating agents open new perspectives for the safe and efficient use of (89) Zr in nuclear imaging, with the best chelators providing dramatically improved stabilities compared with the reference DFB.

Dataset Information

Rational Design, Synthesis and Preliminary Evaluation of Novel Fusarinine C-Based Chelators for Radiolabeling with Zirconium-89.

Publications

Rational Design, Synthesis and Preliminary Evaluation of Novel Fusarinine C-Based Chelators for Radiolabeling with Zirconium-89.

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