Novel Bifunctional Cyclic Chelator for ⁸⁹Zr Labeling–Radiolabeling and Targeting Properties of RGD Conjugates

Abstract

Within the last years 89Zr has attracted considerable attention as long-lived radionuclide for positron emission tomography (PET) applications. So far desferrioxamine B (DFO) has been mainly used as bifunctional chelating system. Fusarinine C (FSC), having complexing properties comparable to DFO, was expected to be an alternative with potentially higher stability due to its cyclic structure. In this study, as proof of principle, various FSC-RGD conjugates targeting αvß3 integrins were synthesized using different conjugation strategies and labeled with 89Zr. In vitro stability, biodistribution, and microPET/CT imaging were evaluated using [89Zr]FSC-RGD conjugates or [89Zr]triacetylfusarinine C (TAFC). Quantitative 89Zr labeling was achieved within 90 min at room temperature. The distribution coefficients of the different radioligands indicate hydrophilic character. Compared to [89Zr]DFO, [89Zr]FSC derivatives showed excellent in vitro stability and resistance against transchelation in phosphate buffered saline (PBS), ethylenediaminetetraacetic acid solution (EDTA), and human serum for up to 7 days. Cell binding studies and biodistribution as well as microPET/CT imaging experiments showed efficient receptor-specific targeting of [89Zr]FSC-RGD conjugates. No bone uptake was observed analyzing PET images indicating high in vivo stability. These findings indicate that FSC is a highly promising chelator for the development of 89Zr-based PET imaging agents.

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for 89Zr ImmunoPET

“…FSC was conjugated to an RGD peptide and showed improved stability over DFO. 37 The prepared 89 Zr-FSC-RGD complexes demonstrated improved stability over 89 Zr-DFO-RGD in in vitro transchelation studies (93.9% stability vs 42.2%, respectively). The cyclic nature of the ligand likely provides greater kinetic stability as it is more difficult for competing materials to access the metal.…”

“…Most recently, Zhai et al 37 have reported a competitive hexadentate ligand based on a derivatized fusarinine C (FSC) molecule (Figure 1). This is a cyclic ligand with a hydroxamate structure very similar to DFO.…”

Comparison of Ga-68-Labeled Fusarinine C-Based Multivalent RGD Conjugates and [68Ga]NODAGA-RGD—In Vivo Imaging Studies in Human Xenograft Tumors

“…FSC(succ-RGD) 3 , FSC(RGDfE) 3 , and FSC(Mal-RGD) 3 were synthesized as described earlier [16]. Milli-Q water was used for preparing all reagent solutions.…”

Siderophores for molecular imaging applications

“…FSC not only allows fast and highly selective labelling with 68 Ga in a wide pH range and results in high specific activities, but also shows very high stability of 68 Ga-FSC complexes at low concentration demonstrating the superiority over DFO which was reported to be unstable at low ligand concentrations (\50 nM) [79]. Compared to 89 Zr-DFO, 89 Zr-FSC derivatives showed excellent in vitro stability and resistance against transchelation in phosphate-buffered saline (PBS), ethylenediaminetetraacetic acid solution (EDTA) and human serum for up to 7 days making it an alternative as 89 Zr BFC [103]. The three primary amines of FSC facilitate the derivatization of FSC with targeting biomolecules in a number of ways, also applying the concept of multivalency.…”

“…Recently, we reported that Fusarinine C (FSC), a representative of the class of hydroxamate siderophores, is a promising 68 Ga and 89 Zr bifunctional chelator [101][102][103][104]. FSC, possessing three hydroxamic acid groups for binding 68 Ga or 89 Zr similar to DFO embedding an additional cyclic structure, offers a potential advantage with respect to the stability of 68 Ga/ 89 Zr complexes.…”