Open this publication in new window or tab >>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
2017-11-242017-10-262018-03-07