PET Tracer Development Targeting the Vesicular Acetylcholine Transporter

Roslin, S. 2017. Exploring Palladium-Mediated C/C-Carbonylation Reactions. PET Tracer Development Targeting the Vesicular Acetylcholine Transporter. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 241. 99 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0136-5. The work presented herein describes the utilization and exploration of palladium-mediated incorporations of carbon monoxide and/or [C]carbon monoxide into compounds and structural motifs with biological relevance. The first part of the thesis describes the design, synthesis and C-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 C/C-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 palladiummediated C/C-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 C-carbonylation for synthesis of C-labeled ureas was described in paper IV. Utilizing only amines in addition to a palladium-source and [C]carbon monoxide, the method proved to be facile and robust, thus representing a simplification in relation to methods using other C-synthons for synthesis of C-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 C-carbonylation reaction to produce C-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 C-labeling of various carbonylated compounds.