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Title: A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging

Abstract

Translation of new 18F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [18F]fluoride of human doses of [18F]5-fluorouracil, a PET tracer for cancer imaging in humans. Here, the first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [18F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18F-fluorination.

Authors:
 [1];  [2];  [3];  [2];  [2];  [2];  [4];  [5]
  1. Harvard Univ., Cambridge, MA (United States)
  2. Univ. of California, Los Angeles, CA (United States)
  3. Harvard Univ., Cambridge, MA (United States); Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States); Massachusetts General Hospital, Boston, MA (United States)
  4. Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States); Massachusetts General Hospital, Boston, MA (United States)
  5. Harvard Univ., Cambridge, MA (United States); Massachusetts General Hospital, Boston, MA (United States); Max-Planck-Institut fur Kohlenforschung, Mulheim an der Ruhr (Germany)
Publication Date:
Research Org.:
Univ. of California, Los Angeles, CA (United States); Massachusetts General Hospital, Boston, MA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1434480
Grant/Contract Number:  
SC0001249; SC0008430
Resource Type:
Accepted Manuscript
Journal Name:
Organometallics
Additional Journal Information:
Journal Volume: 35; Journal Issue: 7; Journal ID: ISSN 0276-7333
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Hoover, Andrew J., Lazari, Mark, Ren, Hong, Narayanam, Maruthi Kumar, Murphy, Jennifer M., van Dam, R. Michael, Hooker, Jacob M., and Ritter, Tobias. A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging. United States: N. p., 2016. Web. doi:10.1021/acs.organomet.6b00059.
Hoover, Andrew J., Lazari, Mark, Ren, Hong, Narayanam, Maruthi Kumar, Murphy, Jennifer M., van Dam, R. Michael, Hooker, Jacob M., & Ritter, Tobias. A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging. United States. doi:10.1021/acs.organomet.6b00059.
Hoover, Andrew J., Lazari, Mark, Ren, Hong, Narayanam, Maruthi Kumar, Murphy, Jennifer M., van Dam, R. Michael, Hooker, Jacob M., and Ritter, Tobias. Sun . "A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging". United States. doi:10.1021/acs.organomet.6b00059. https://www.osti.gov/servlets/purl/1434480.
@article{osti_1434480,
title = {A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging},
author = {Hoover, Andrew J. and Lazari, Mark and Ren, Hong and Narayanam, Maruthi Kumar and Murphy, Jennifer M. and van Dam, R. Michael and Hooker, Jacob M. and Ritter, Tobias},
abstractNote = {Translation of new 18F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [18F]fluoride of human doses of [18F]5-fluorouracil, a PET tracer for cancer imaging in humans. Here, the first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [18F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18F-fluorination.},
doi = {10.1021/acs.organomet.6b00059},
journal = {Organometallics},
number = 7,
volume = 35,
place = {United States},
year = {2016},
month = {2}
}

Journal Article:
Free Publicly Available Full Text
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Cited by: 20 works
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Figures / Tables:

Scheme 1 Scheme 1: Strategy for the Synthesis of [18F]5-Fluorouracil

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Works referencing / citing this record:

Carbon-Fluorine Reductive Elimination from Nickel(III) Complexes
journal, May 2017

  • Lee, Heejun; Börgel, Jonas; Ritter, Tobias
  • Angewandte Chemie International Edition, Vol. 56, Issue 24
  • DOI: 10.1002/anie.201701552

Bioconjugated arylpalladium complexes on solid supports for a convenient last-step synthesis of 11 C-labelled tracers for positron emission tomography
journal, January 2019

  • Tabey, Alexis; Audrain, Hélène; Fouquet, Eric
  • Chemical Communications, Vol. 55, Issue 53
  • DOI: 10.1039/c9cc03215k

Fast and efficient copper-mediated 18F-fluorination of arylstannanes, aryl boronic acids, and aryl boronic esters without azeotropic drying
journal, October 2019

  • Lahdenpohja, Salla Orvokki; Rajala, Noora Annika; Rajander, Johan
  • EJNMMI Radiopharmacy and Chemistry, Vol. 4, Issue 1
  • DOI: 10.1186/s41181-019-0079-y

Carbon-Fluorine Reductive Elimination from Nickel(III) Complexes
journal, May 2017

  • Lee, Heejun; Börgel, Jonas; Ritter, Tobias
  • Angewandte Chemie International Edition, Vol. 56, Issue 24
  • DOI: 10.1002/anie.201701552

Automated synthesis of PET radiotracers by copper-mediated 18 F-fluorination of organoborons: Importance of the order of addition and competing protodeborylation
journal, February 2018

  • Mossine, Andrew V.; Brooks, Allen F.; Bernard-Gauthier, Vadim
  • Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 61, Issue 3
  • DOI: 10.1002/jlcr.3583

Bioconjugated arylpalladium complexes on solid supports for a convenient last-step synthesis of 11 C-labelled tracers for positron emission tomography
journal, January 2019

  • Tabey, Alexis; Audrain, Hélène; Fouquet, Eric
  • Chemical Communications, Vol. 55, Issue 53
  • DOI: 10.1039/c9cc03215k

Fast and efficient copper-mediated 18F-fluorination of arylstannanes, aryl boronic acids, and aryl boronic esters without azeotropic drying
journal, October 2019

  • Lahdenpohja, Salla Orvokki; Rajala, Noora Annika; Rajander, Johan
  • EJNMMI Radiopharmacy and Chemistry, Vol. 4, Issue 1
  • DOI: 10.1186/s41181-019-0079-y

Carbon-Fluorine Reductive Elimination from Nickel(III) Complexes
journal, May 2017

  • Lee, Heejun; Börgel, Jonas; Ritter, Tobias
  • Angewandte Chemie, Vol. 129, Issue 24
  • DOI: 10.1002/ange.201701552

Synthesis of [ 18 F]Fluoroarenes by Nucleophilic Radiofluorination of N -Arylsydnones
journal, September 2017

  • Narayanam, Maruthi Kumar; Ma, Gaoyuan; Champagne, Pier Alexandre
  • Angewandte Chemie, Vol. 129, Issue 42
  • DOI: 10.1002/ange.201707274

Chemie der Positronenemissionstomographie: Aktuelle Fortschritte bei 11 C‐, 18 F‐, 13 N‐ und 15 O‐Markierungsreaktionen
journal, January 2019


Chemistry for Positron Emission Tomography: Recent Advances in 11 C-, 18 F-, 13 N-, and 15 O-Labeling Reactions
journal, January 2019

  • Deng, Xiaoyun; Rong, Jian; Wang, Lu
  • Angewandte Chemie International Edition, Vol. 58, Issue 9
  • DOI: 10.1002/anie.201805501

Radiosynthesis of the norepinephrine transporter tracer [ 18 F]NS12137 via copper-mediated 18 F-labelling
journal, May 2019

  • Lahdenpohja, Salla; Keller, Thomas; Rajander, Johan
  • Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 62, Issue 6
  • DOI: 10.1002/jlcr.3717

Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium( iii ) ylides
journal, January 2016

  • Rotstein, Benjamin H.; Wang, Lu; Liu, Richard Y.
  • Chemical Science, Vol. 7, Issue 7
  • DOI: 10.1039/c6sc00197a

One-pot synthesis of high molar activity 6-[ 18 F]fluoro- l -DOPA by Cu-mediated fluorination of a BPin precursor
journal, January 2019

  • Mossine, Andrew V.; Tanzey, Sean S.; Brooks, Allen F.
  • Organic & Biomolecular Chemistry, Vol. 17, Issue 38
  • DOI: 10.1039/c9ob01758e

Fluorination methods for drug discovery and development
journal, August 2016


Alcohol-Supported Cu-Mediated 18F-Fluorination of Iodonium Salts under “Minimalist” Conditions
journal, September 2019

  • Orlovskaya, Victoriya V.; Modemann, Daniel J.; Kuznetsova, Olga F.
  • Molecules, Vol. 24, Issue 17
  • DOI: 10.3390/molecules24173197

Fluorinated nucleosides as an important class of anticancer and antiviral agents
journal, October 2017

  • Cavaliere, Alessandra; Probst, Katrin C.; Westwell, Andrew D.
  • Future Medicinal Chemistry, Vol. 9, Issue 15
  • DOI: 10.4155/fmc-2017-0095

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