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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. https://doi.org/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. https://doi.org/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:
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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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