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Theranostics 2017; 7(11):2924-2939. doi:10.7150/thno.20094 This issue Cite

Research Paper

Al¹⁸F-Labeling Of Heat-Sensitive Biomolecules for Positron Emission Tomography Imaging

Frederik Cleeren¹, Joan Lecina¹, Muneer Ahamed¹, Geert Raes^{2, 3}, Nick Devoogdt⁴, Vicky Caveliers⁴, Paul McQuade⁵, Daniel J Rubins⁵, Wenping Li⁵, Alfons Verbruggen¹, Catarina Xavier⁴, Guy Bormans^1✉

1. Laboratory for Radiopharmaceutical research, Department of Pharmacy and Pharmacology, University of Leuven, Leuven, Belgium;
2. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium;
3. VIB Laboratory of Myeloid Cell Immunology, Vrije Universiteit Brussel, Brussels, Belgium;
4. In Vivo Cellular and Molecular Imaging Center, Vrije Universiteit Brussel, Brussels, Belgium;
5. Translational Biomarkers, Merck Research Laboratories, Merck & Co., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.

✉ Corresponding author.

Abstract

Positron emission tomography (PET) using radiolabeled biomolecules is a translational molecular imaging technology that is increasingly used in support of drug development. Current methods for radiolabeling biomolecules with fluorine-18 are laborious and require multistep procedures with moderate labeling yields. The Al¹⁸F-labeling strategy involves chelation in aqueous medium of aluminum mono[¹⁸F]fluoride ({Al¹⁸F}²⁺) by a suitable chelator conjugated to a biomolecule. However, the need for elevated temperatures (100-120 °C) required for the chelation reaction limits its widespread use. Therefore, we designed a new restrained complexing agent (RESCA) for application of the AlF strategy at room temperature.

Methods. The new chelator RESCA was conjugated to three relevant biologicals and the constructs were labeled with {Al¹⁸F}²⁺ to evaluate the generic applicability of the one-step Al¹⁸F-RESCA-method.

Results. We successfully labeled human serum albumin with excellent radiochemical yields in less than 30 minutes and confirmed in vivo stability of the Al¹⁸F-labeled protein in rats. In addition, we efficiently labeled nanobodies targeting the Kupffer cell marker CRIg, and performed µPET studies in healthy and CRIg deficient mice to demonstrate that the proposed radiolabeling method does not affect the functional integrity of the protein. Finally, an affibody targeting HER2 (PEP04314) was labeled site-specifically, and the distribution profile of (±)-[¹⁸F]AlF(RESCA)-PEP04314 in a rhesus monkey was compared with that of [¹⁸F]AlF(NOTA)-PEP04314 using whole-body PET/CT.

Conclusion. This generic radiolabeling method has the potential to be a kit-based fluorine-18 labeling strategy, and could have a large impact on PET radiochemical space, potentially enabling the development of many new fluorine-18 labeled protein-based radiotracers.

Keywords: Al¹⁸F-labeling, PET, human serum albumin, nanobody, affibody.

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