uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.ORCID iD: 0000-0003-0199-5196
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.ORCID iD: 0000-0002-2885-2016
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-6258-0635
Show others and affiliations
2017 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 10, article id 1688Article in journal (Refereed) Published
Abstract [en]

Positron emission tomography is an imaging technique with applications in clinical settings as well as in basic research for the study of biological processes. A PET tracer, a biologically active molecule where a positron-emitting radioisotope such as carbon-11 has been incorporated, is used for the studies. Development of robust methods for incorporation of the radioisotope is therefore of the utmost importance. The urea functional group is present in many biologically active compounds and is thus an attractive target for incorporation of carbon-11 in the form of [C-11] carbon monoxide. Starting with amines and [C-11] carbon monoxide, both symmetrical and unsymmetrical C-11-labelled ureas were synthesised via a palladium(II)-mediated oxidative carbonylation and obtained in decay-corrected radiochemical yields up to 65%. The added advantage of using [C-11] carbon monoxide was shown by the molar activity obtained for an inhibitor of soluble epoxide hydrolase (247 GBq/mu mol-319 GBq/mu mol). DFT calculations were found to support a reaction mechanism proceeding through an C-11-labelled isocyanate intermediate.

Place, publisher, year, edition, pages
2017. Vol. 22, no 10, article id 1688
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-332289DOI: 10.3390/molecules22101688ISI: 000414670600115OAI: oai:DiVA.org:uu-332289DiVA, id: diva2:1152907
Available from: 2017-10-26 Created: 2017-10-26 Last updated: 2018-03-12Bibliographically approved
In thesis
1. Exploring Palladium-Mediated 11C/12C-Carbonylation Reactions: PET Tracer Development Targeting the Vesicular Acetylcholine Transporter
Open this publication in new window or tab >>Exploring Palladium-Mediated 11C/12C-Carbonylation Reactions: PET Tracer Development Targeting the Vesicular Acetylcholine Transporter
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work presented herein describes the utilization and exploration of palladium-mediated incorporations of carbon monoxide and/or [11C]carbon monoxide into compounds and structural motifs with biological relevance.

The first part of the thesis describes the design, synthesis and 11C-labeling of prospective PET tracers for the vesicular acetylcholine transporter (VAChT), a target affected in several neurodegenerative diseases. Different parts of the benzovesamicol scaffold were modified in papers I and II to probe the binding to VAChT. The key motif was an amide functional group, which enabled the use of palladium-mediated 11C/12C-carbonylations to synthesize and evaluate two different sets of structurally related ligands.

The second part of the thesis describes the exploration of different aspects of palladium-mediated 11C/12C-carbonylation reactions. The utilization of unactivated alkyl iodides and bromides as coupling partners in a carbonylative Suzuki-Miyaura reaction was described in paper III. The combination of palladium-catalysis together with visible light irradiation enabled their functionalization via an alkyl radical. The mild conditions, namely the ambient temperature and pressure of carbon monoxide, and the accessible reaction set-up further added to the utility of the method. A palladium(II)-mediated oxidative 11C-carbonylation for synthesis of 11C-labeled ureas was described in paper IV. Utilizing only amines in addition to a palladium-source and [11C]carbon monoxide, the method proved to be facile and robust, thus representing a simplification in relation to methods using other 11C-synthons for synthesis of 11C-labeled ureas. Finally, a palladium(0)-catalyzed carbonylation reaction for synthesis of acylamidines was presented in paper V. The versatility of the method was demonstrated by one-pot cyclizations to form oxadiazoles and triazoles together with the corresponding 11C-carbonylation reaction to produce 11C-labeled acylamidines and an oxadiazole.

The work described herein has thus contributed structural information in the search for a PET tracer for VAChT and identified a viable lead structure for future investigations. Furthermore, investigation of reaction conditions that would allow use of either elusive or accessible substrates led to the development of methods for synthesis and/or 11C-labeling of various carbonylated compounds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 99
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 241
Keywords
Carbonylation, palladium, carbon-11, radiochemistry, positron emission tomography, vesicular acetylcholine transporter, vesamicol, alkyl halide, oxidative carbonylation, acylamidine, oxadiazole, heterocycle
National Category
Organic Chemistry Other Chemistry Topics
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-332359 (URN)978-91-513-0136-5 (ISBN)
Public defence
2017-12-15, Hall B:21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-11-24 Created: 2017-10-26 Last updated: 2018-03-07

Open Access in DiVA

fulltext(3761 kB)37 downloads
File information
File name FULLTEXT01.pdfFile size 3761 kBChecksum SHA-512
ba2ec0a9beaa158304442a27ade26715b15a9fe31a5e0ce20532b1fc3cb8afe08a8c791b9767d45e07eeb81ae7f120638cbd6028ee348879128ebb1336be75f9
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Authority records BETA

Bergman, SaraBrandt, PeterNordeman, PatrikLarhed, MatsOdell, Luke R.Eriksson, Jonas

Search in DiVA

By author/editor
Bergman, SaraBrandt, PeterNordeman, PatrikLarhed, MatsOdell, Luke R.Eriksson, Jonas
By organisation
Organic Pharmaceutical ChemistryScience for Life Laboratory, SciLifeLab
In the same journal
Molecules
Organic Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 37 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 107 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf