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Biomolecules 2019, 9(3), 91; https://doi.org/10.3390/biom9030091

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

1
School of Forensic Medicine, Southern Medical University, 510515 Guangzhou, China
2
Department of Nuclear Medicine, Medical University Innsbruck, 6020 Innsbruck, Austria
3
Department of Nuclear Medicine, Guangdong Academy of Medical Sciences, 510080 Guangzhou, China
4
Division of Molecular Biology, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria
5
Division of Clinical Biochemistry, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria
6
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, E1 4NS London, UK
*
Author to whom correspondence should be addressed.
Received: 23 November 2018 / Revised: 4 February 2019 / Accepted: 25 February 2019 / Published: 6 March 2019
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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)2 and FSC(succ)3. FSC(succ)2 was further derivatized to FSC(succ)2 AA by reacting with acetic anhydride (AA). The Zr4+ complexation properties of these chelators were studied by reacting with ZrCl4. 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)3 were further compared with [89Zr]Zr-TAFC in BALB/c mice using micro-positron emission tomography/computer tomography (microPET/CT) imaging. Fusarinine C (succ)2AA and FSC(succ)3 were synthesized with satisfactory yields. Complexation with ZrCl4 was achieved using a simple strategy resulting in high-purity Zr-FSC(succ)2AA and Zr-FSC(succ)3 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)3 > [89Zr]Zr-TAFC > [89Zr]Zr-FSC(succ)2AA >> [89Zr]Zr-DFO. Biodistribution studies of [89Zr]Zr-FSC(succ)3 revealed a slower excretion pattern compared to [89Zr]Zr-TAFC. In conclusion, [89Zr]Zr-FSC(succ)3 showed the best stability and inertness. The promising results obtained with [89Zr]Zr-FSC(succ)2AA highlight the potential of FSC(succ)2 as a monovalent chelator for conjugation to targeted biomolecules, in particular, monoclonal antibodies. View Full-Text
Keywords: fusarinine C (FSC); zirconium-89; bifunctional chelator; immuno-positron emission tomography (PET) fusarinine C (FSC); zirconium-89; bifunctional chelator; immuno-positron emission tomography (PET)
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Zhai, C.; He, S.; Ye, Y.; Rangger, C.; Kaeopookum, P.; Summer, D.; Haas, H.; Kremser, L.; Lindner, H.; Foster, J.; Sosabowski, J.; Decristoforo, C. Rational Design, Synthesis and Preliminary Evaluation of Novel Fusarinine C-Based Chelators for Radiolabeling with Zirconium-89. Biomolecules 2019, 9, 91.

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