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Radiosynthesis of [18F]SiFAlin-TATE for clinical neuroendocrine tumor positron emission tomography

Nature Protocols volume 15, pages 3827–3843 (2020)Cite this article

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Abstract

Here, we describe an extension of our silicon fluoride acceptor (SiFA) protocol for 18F-labeling of peptides that addresses challenges associated with preparing a clinical-grade (Tyr3)-octreotate (TATE) tracer for diagnosis of neuroendocrine tumors (NETs). After several iterations of protocol optimization (e.g., finding the optimal pH at which the isotopic exchange (IE) reaction produces high radiochemical yields (RCYs)), the SiFA technology achieved clinical applicability, as showcased by radiosynthesis of [18F]SiFAlin-TATE ([18F]SiTATE), the first SiFA peptide used in the clinical diagnosis of NETs. The TATE peptide binds to somatostatin receptors associated with NETs. Radiolabeled TATE derivatives are routinely applied in clinical oncological PET imaging. The (SiFA) 18F-labeling technology is based on the IE of a 19F atom for a radioactive 18F atom, a highly efficient labeling reaction under mild conditions. The 19F is part of a biomolecule bearing the SiFA building block, composed of a central silicon (Si) atom, a 19F atom connected to the Si atom, and two Si-bound tert-butyl groups. The IE proceeds through a penta-coordinate bipyramidal intermediate, followed by elimination of non-radioactive 19F, yielding the labeled compound in high RCYs at room temperature (22 °C). The simplicity and lack of side-product formation of this approach enable a one-step, kit-like preparation of structurally complex and unprotected radiopharmaceuticals. Compounds such as peptides used for tumor imaging in nuclear medicine can be 18F-labeled without the need for complex purification protocols. [18F]SiTATE can be synthesized within 30 min in preparative RCYs of 42%, radiochemical purity of >97% and high molar activity of 60 GBq/µmol.

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Fig. 1: Molecular structure of SiTATE.
Fig. 2: Flow chart for the synthesis of [18F]SiTATE.
Fig. 3: Typical HPLC chromatogram of semipreparative HPLC purification of SiTATE(7).
Fig. 4: Synthesis of [18F]SiTATE [18F]7.
Fig. 5: HPLC chromatograms of purified [18F]SiTATE [18F]7 and the unlabeled reference compound 7. [18F]SiTATE [18F]7, blue, retention time 2.4 min; unlabeled reference compound 7, orange.

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Data availability

Figures 3 and 5 show example HPLC chromatograms. These data are shown for the first time in these figures. Figure 4 includes information about the yields of the reactions, and the Anticipated results section contains their analytical data; these have been described in previous work, except for compound 7, which is included in this article.

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Acknowledgements

Funding for this research was provided by the Natural Sciences and Engineering Research Council of Canada (NSERC, Discovery Grant) to R.S.

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Author notes

  1. These authors contributed equally: Simon Lindner, Carmen Wängler.

  2. These authors jointly supervised this work: Björn Wängler, Ralf Schirrmacher.

Authors and Affiliations

  1. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany

    Simon Lindner & Peter Bartenstein

  2. Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Faculty of Medicine Mannheim, Heidelberg University, Mannheim, Germany

    Carmen Wängler

  3. Cross Cancer Institute, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

    Justin J. Bailey & Ralf Schirrmacher

  4. Department of Chemistry, Fakultät für Chemie und Chemische Biologie, Technische Universität Dortmund, Dortmund, Germany

    Klaus Jurkschat

  5. Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Faculty of Medicine Mannheim, Heidelberg University, Mannheim, Germany

    Björn Wängler

  6. Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada

    Ralf Schirrmacher

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Contributions

S.L. and C.W. performed the chemistry/radiochemistry, developed the protocol and helped writing the materials, procedure and troubelshooting paragraphs. C.W., J.J.B., K.J., P.B. and B.W. co-developed the protocol and wrote parts of the protocol. R.S. and B. W. developed the protocol and wrote the abstract and introduction of the protocol.

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Correspondence to Björn Wängler or Ralf Schirrmacher.

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Peer review information Nature Protocols thanks Bernd Neumaier and Chris Phenix for their contribution to the peer review of this work.

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Key references using this protocol

Niedermoser, S. et al. J. Nucl. Med. 56, 1100–1105 (2015): http://jnm.snmjournals.org/content/56/7/1100.long

Ilhan, H. et al. Eur. J. Nucl. Med. Mol. Imaging 47, 870–880 (2020): https://link.springer.com/article/10.1007/s00259-019-04501-6

Ilhan, H. et al. Eur. J. Nucl. Med. Mol. Imaging 46, 2400–2401 (2019): https://link.springer.com/article/10.1007%2Fs00259-019-04448-8

Related protocol

Wängler, B. et al. Nat. Prot. 7, 1964–1969 (2012): https://doi.org/10.1038/nprot.2012.111

This protocol is an extension to: Nat. Protoc. 7, 1946–1955 (2012): https://doi.org/10.1038/nprot.2012.109

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Lindner, S., Wängler, C., Bailey, J.J. et al. Radiosynthesis of [18F]SiFAlin-TATE for clinical neuroendocrine tumor positron emission tomography. Nat Protoc 15, 3827–3843 (2020). https://doi.org/10.1038/s41596-020-00407-y

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