Facile 18f labeling of non-activated arenes via a spirocyclic iodonium(iii) ylide method and its application in the synthesis of the mglur5 pet radiopharmaceutical [18f]fpeb

ABSTRACT Non-activated (electron-rich and/or sterically hindered) arenes are prevalent chemical scaffolds in pharmaceuticals and positron emission tomography (PET) diagnostics. Despite

substantial efforts to develop a general method to introduce 18F into these moieties for molecular imaging by PET, there is an urgent and unmet need for novel radiofluorination strategies

that result in sufficiently labeled tracers to enable human imaging. Herein, we describe an efficient method that relies on spirocyclic iodonium ylide (SCIDY) precursors for one-step and

regioselective radiofluorination, as well as proof-of-concept translation to the radiosynthesis of a clinically useful PET tracer, 3-[18F]fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile

([18F]FPEB). The protocol begins with the preparation of a SCIDY precursor for FPEB, followed by radiosynthesis of [18F]FPEB, by either manual operation or an automated synthesis module.

[18F]FPEB can be obtained in quantities >7.4 GBq (200 mCi), ready for injection (20 ± 5%, non–decay corrected), and has excellent chemical and radiochemical purity (>98%) as well as

high molar activity (666 ± 51.8 GBq/μmol; 18 ± 1.4 Ci/μmol). The total time for the synthesis and purification of the corresponding labeling SCIDY precursor is 10 h. The subsequent

radionuclide production, experimental setup, 18F labeling, and formulation of a product that is ready for injection require 2 h. Access through your institution Buy or subscribe This is a

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HALIDE INTERCONVERSION Article 13 December 2021 METALLAPHOTOREDOX ARYL AND ALKYL RADIOMETHYLATION FOR PET LIGAND DISCOVERY Article 25 November 2020 [18F]TOSYL FLUORIDE AS A VERSATILE

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ACKNOWLEDGEMENTS We thank X. Zhang and Z. Chen for technical support and members of the staff in the radiochemistry and radiopharmaceutical development program at MGH for helpful

discussions. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical

School, Boston, MA, USA Steven H. Liang, Lu Wang, Nickeisha A. Stephenson, Benjamin H. Rotstein & Neil Vasdev Authors * Steven H. Liang View author publications You can also search for

this author inPubMed Google Scholar * Lu Wang View author publications You can also search for this author inPubMed Google Scholar * Nickeisha A. Stephenson View author publications You can

also search for this author inPubMed Google Scholar * Benjamin H. Rotstein View author publications You can also search for this author inPubMed Google Scholar * Neil Vasdev View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS S.H.L., L.W., N.A.S., and B.H.R. performed the experimental work. S.H.L. and N.V. oversaw the

radiopharmaceutical production. All authors wrote the manuscript. CORRESPONDING AUTHOR Correspondence to Steven H. Liang. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no

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LINKS KEY REFERENCES USING THIS PROTOCOL Rotstein, B.H., Stephenson, N.A., Vasdev, N. & Liang, S.H_. Nat. Commun_. 5, 4365 (2014): https://www.nature.com/articles/ncomms5365 Rotstein,

B.H. et al_. Chem. Sci_. 7, 4407–4417 (2016): https://pubs.rsc.org/en/content/articlelanding/2016/sc/c6sc00197a#!divAbstract Stephenson, N.A. et al. _J. Nucl. Med_. 56, 489–492 (2015):

http://jnm.snmjournals.org/content/56/3/489.long Wang, L. et al. _J. Med. Chem_. 60, 5222–5227 (2017): https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00432 KEY DATA USED IN THIS PROTOCOL

Rotstein, B.H., Stephenson, N.A., Vasdev, N. & Liang, S.H. _Nat. Commun_. 5, 4365 (2014): https://www.nature.com/articles/ncomms5365 Stephenson, N.A. et al. _J. Nucl. Med_. 56, 489–492

(2015): http://jnm.snmjournals.org/content/56/3/489.long SUPPLEMENTARY INFORMATION REPORTING SUMMARY RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Liang, S.H., Wang, L., Stephenson, N.A. _et al._ Facile 18F labeling of non-activated arenes via a spirocyclic iodonium(III) ylide method and its application in the synthesis of the mGluR5

PET radiopharmaceutical [18F]FPEB. _Nat Protoc_ 14, 1530–1545 (2019). https://doi.org/10.1038/s41596-019-0149-3 Download citation * Received: 13 June 2017 * Accepted: 12 February 2019 *

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