An octadentate bifunctional chelating agent for the development of stable zirconium-89 based molecular imaging probes

Patra, Malay; Bauman, Andreas; Mari, Cristina; Fischer, Christian; Blacque, Olivier; Häußinger, Daniel; Gasser, Gilles; Mindt, Thomas L.

doi:10.1039/c4cc05558f

Cited by 133 publications

(166 citation statements)

References 14 publications

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“…In a similar study, an octadentate derivative of DFO called DFO* (Figure 1), containing an additional hydroxamate group was also shown to chelate zirconium well. 35 The complex of Zr 4+ with this octadentate DFO* was predicted to be more stable than that with hexadentate DFO by DFT calculations. A bifunctional derivative, DFO*–CO 2 H, was also created and conjugated to bombesin for preliminary evaluation and was shown to be significantly more stable than 89 Zr-DFO-bombesin in in vitro challenge studies over 24 h. No additional stability experiments were reported for longer time points or conditions.…”

Section: Resultsmentioning

confidence: 93%

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

et al. 2015

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Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the 89Zr4+ cation is being released in vivo. Therefore, a more robust chelator for 89Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of 89Zr4+ and high stability; therefore, we developed a bifunctional derivative, p-SCN-Bn-HOPO, for conjugation to an antibody. A Zr-HOPO crystal structure was obtained showing that the Zr is fully coordinated by the octadentate HOPO ligand, as expected, forming a stable complex. p-SCN-Bn-HOPO was synthesized through a novel pathway. Both p-SCN-Bn-HOPO and p-SCN-Bn-DFO were conjugated to trastuzumab and radiolabeled with 89Zr. Both complexes labeled efficiently and achieved specific activities of approximately 2 mCi/mg. PET imaging studies in nude mice with BT474 tumors (n = 4) showed good tumor uptake for both compounds, but with a marked decrease in bone uptake for the 89Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for 89Zr-DFO-trastuzumab while 89Zr-HOPO-trastuzumab only had 2.4%ID/g. We successfully synthesized p-SCN-Bn-HOPO, a bifunctional derivative of 3,4,3-(LI-1,2-HOPO) as a potential chelator for 89Zr. In vivo studies demonstrate the successful use of 89Zr-HOPO-trastuzumab to image BT474 breast cancer with low background, good tumor to organ contrast, and, importantly, very low bone uptake. The reduced bone uptake seen with 89Zr-HOPO-trastuzumab suggests superior stability of the 89Zr-HOPO complex.

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Section: Resultsmentioning

confidence: 93%

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

et al. 2015

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“…DFO*- p Phe-NCS was prepared from DFO* [24] in a single step by reaction with p -phenylenediisothiocyanate (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we reported the synthesis of DFO* and the superior in vitro stability of its complex with 89 Zr in comparison to 89 Zr-DFO, also when challenged with an excess of DFO [24]. Here, we describe the synthesis of a bifunctional version of this chelator, DFO*- p Phe-NCS.…”

Section: Discussionmentioning

confidence: 98%

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Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET

Vugts

Klaver

Sewing

et al. 2016

Eur J Nucl Med Mol Imaging

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123

150

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PurposeAll clinical 89Zr-immuno-PET studies are currently performed with the chelator desferrioxamine (DFO). This chelator provides hexadentate coordination to zirconium, leaving two coordination sites available for coordination with, e.g., water molecules, which are relatively labile ligands. The unsaturated coordination of DFO to zirconium has been suggested to result in impaired stability of the complex in vivo and consequently in unwanted bone uptake of 89Zr. Aiming at clinical improvements, we report here on a bifunctional isothiocyanate variant of the octadentate chelator DFO* and the in vitro and in vivo comparison of its 89Zr-DFO*-mAb complex with 89Zr-DFO-mAb.MethodsThe bifunctional chelator DFO*-pPhe-NCS was prepared from previously reported DFO* and p-phenylenediisothiocyanate. Subsequently, trastuzumab was conjugated with either DFO*-pPhe-NCS or commercial DFO-pPhe-NCS and radiolabeled with Zr-89 according to published procedures. In vitro stability experiments were carried out in saline, a histidine/sucrose buffer, and blood serum. The in vivo performance of the chelators was compared in N87 tumor-bearing mice by biodistribution studies and PET imaging.ResultsIn 0.9 % NaCl 89Zr-DFO*-trastuzumab was more stable than 89Zr-DFO-trastuzumab; after 72 h incubation at 2-8 °C 95 % and 58 % intact tracer were left, respectively, while in a histidine-sucrose buffer no difference was observed, both products were ≥ 92 % intact. In vivo uptake at 144 h post injection (p.i.) in tumors, blood, and most normal organs was similar for both conjugates, except for skin, liver, spleen, ileum, and bone. Tumor uptake was 32.59 ± 11.95 and 29.06 ± 8.66 % ID/g for 89Zr-DFO*-trastuzumab and 89Zr-DFO-trastuzumab, respectively. The bone uptake was significantly lower for 89Zr-DFO*-trastuzumab compared to 89Zr-DFO-trastuzumab. At 144 h p.i. for 89Zr-DFO*-trastuzumab and 89Zr-DFO-trastuzumab, the uptake in sternum was 0.92 ± 0.16 and 3.33 ± 0.32 % ID/g, in femur 0.78 ± 0.11 and 3.85, ± 0.80 and in knee 1.38 ± 0.23 and 8.20 ± 2.94 % ID/g, respectively. The uptake in bone decreased from 24 h to 144 h p.i. about two fold for the DFO* conjugate, while it increased about two fold for the DFO conjugate.ConclusionsZr-DFO*-trastuzumab showed superior in vitro stability and in vivo performance when compared to 89Zr-DFO-trastuzumab. This makes the new octadentate DFO* chelator a candidate successor of DFO for future clinical 89Zr-immuno-PET.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3499-x) contains supplementary material, which is available to authorised users.

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“…This insufficient stability of the 89 Zr-DFO complexes is attributed to the incomplete coordination of 89 Zr 4? by DFO and the linear structure of DFO. Based on the knowledge of DFO, Patra et al developed an octadentate DFO analogue termed DFO*, which fully saturates the coordination sphere of Zr 4? , by coupling an additional hydroxamic acid entity to DFO [100]. DFT calculations predicted the expected molecular structure involving coordination through the eight oxygen atoms of all four hydroxamic acid moieties.…”

Section: Improvement Of Dfo Formentioning

confidence: 99%

Siderophores for molecular imaging applications

Petřík

Zhai

Haas

et al. 2016

Clin Transl Imaging

110

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This review covers publications on siderophores applied for molecular imaging applications, mainly for radionuclide-based imaging. Siderophores are low molecular weight chelators produced by bacteria and fungi to scavenge essential iron. Research on these molecules has a continuing history over the past 50 years. Many biomedical applications have been developed, most prominently the use of the siderophore desferrioxamine (DFO) to tackle iron overload related diseases. Recent research described the upregulation of siderophore production and transport systems during infection. Replacing iron in siderophores by radionuclides, the most prominent Ga-68 for PET, opens approaches for targeted imaging of infection; the proof of principle has been reported for fungal infections using 68 Ga-triacetylfusarinine C (TAFC). Additionally, fluorescent siderophores and therapeutic conjugates have been described and may be translated to optical imaging and theranostic applications. Siderophores have also been applied as bifunctional chelators, initially DFO as chelator for Ga-67 and more recently for Zr-89 where it has become the standard chelator in Immuno-PET. Improved DFO constructs and bifunctional chelators based on cyclic siderophores have recently been developed for Ga-68 and Zr-89 and show promising properties for radiopharmaceutical development in PET. A huge potential from basic biomedical research on siderophores still awaits to be utilized for clinical and translational imaging.

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An octadentate bifunctional chelating agent for the development of stable zirconium-89 based molecular imaging probes

Cited by 133 publications

References 14 publications

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

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

Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET

Siderophores for molecular imaging applications

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An octadentate bifunctional chelating agent for the development of stable zirconium-89 based molecular imaging probes

Cited by 133 publications

References 14 publications

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

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

Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET

Siderophores for molecular imaging applications

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Product

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

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