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.
Highlights
Immuno-positron emission tomography (PET) is of great value for the development of monoclonal antibodies as therapeutic targeting vectors,(PET)enabling and quantification of radiolabeledImmuno-positron emission tomography is oftracking great value for the development of mAbs at highantibodies resolution(mAbs) and sensitivity [1]. targetingIn recent years,enabling Zirconium-89Zr), in particular, monoclonal as therapeutic vectors, tracking(and quantification hasofbecome the most commonly-studied forZirconium-89 immuno-PET radiolabeled mAbs at high resolution positron-emitting and sensitivity [1]. radionuclide In recent years
We reported that fusarinine C (FSC), which has a 36-membered ring structure and three bidentate hydroxamates to coordinate 89 Zr, showed superior stability and kinetic inertness compared to DFO
The straightforward synthesis of FSC(succ)2 acetic anhydride (AA) and FSC(succ)3 is shown in Scheme 1
Summary
Immuno-positron emission tomography (PET) is of great value for the development of monoclonal antibodies (mAbs) as therapeutic targeting vectors,(PET)enabling and quantification of radiolabeledImmuno-positron emission tomography is oftracking great value for the development of mAbs at highantibodies resolution(mAbs) and sensitivity [1]. targetingIn recent years,enabling Zirconium-89Zr), in particular, monoclonal as therapeutic vectors, tracking(and quantification hasofbecome the most commonly-studied forZirconium-89 immuno-PET radiolabeled mAbs at high resolution positron-emitting and sensitivity [1]. radionuclide In recent years, Immuno-positron emission tomography (PET) is of great value for the development of monoclonal antibodies (mAbs) as therapeutic targeting vectors,(PET). Immuno-positron emission tomography is oftracking great value for the development of mAbs at highantibodies resolution(mAbs) and sensitivity [1]. Zr), in particular, monoclonal as therapeutic vectors, tracking(and quantification hasofbecome the most commonly-studied forZirconium-89 immuno-PET radiolabeled mAbs at high resolution positron-emitting and sensitivity [1]. 78.4 h is a good match with the biological half-life of mAbs, increasing particular, has become the most commonly-studied positron-emitting radionuclide for immuno-PET theimaging
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