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Exploring Palladium-Mediated 11C/12C-Carbonylation Reactions: PET Tracer Development Targeting the Vesicular Acetylcholine Transporter
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.ORCID iD: 0000-0003-0199-5196
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 [en]
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: urn:nbn:se:uu:diva-332359ISBN: 978-91-513-0136-5 (print)OAI: oai:DiVA.org:uu-332359DiVA, id: diva2:1152964
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
List of papers
1. Synthesis and Labelling of a Piperazine-Based Library of 11C-Labeled Ligands for Imaging of the Vesicular Acetylcholine Transporter
Open this publication in new window or tab >>Synthesis and Labelling of a Piperazine-Based Library of 11C-Labeled Ligands for Imaging of the Vesicular Acetylcholine Transporter
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2014 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 57, no 8, p. 525-532Article in journal (Refereed) Published
Abstract [en]

The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a-f, six potential VAChT PET tracers, [C-11]-(+/-)5a-f, were C-11-labeled by a palladium (0)-mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [C-11]-(+/-)5a-f were obtained in radiochemical purities >95% with decay-corrected radiochemical yields and specific radioactivities between 4-25% and 124-597 GBq/mu mol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [C-11]-(+/-)5d and [C-11]-(+/-)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine-based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach.

Keywords
vesicular acetylcholine transporter, carbonylation, PET, library, C-11-labeling, vesamicol
National Category
Radiology, Nuclear Medicine and Medical Imaging Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-231333 (URN)10.1002/jlcr.3208 (DOI)000340169500004 ()24991704 (PubMedID)
Available from: 2014-09-07 Created: 2014-09-07 Last updated: 2018-01-11
2. Synthesis and In Vitro Evaluation of 5-Substituted Benzovesamicol Analogs containing N-Substituted Amides as Potential Positron Emission Tomography Tracers for the Vesicular Acetylcholine Transporter
Open this publication in new window or tab >>Synthesis and In Vitro Evaluation of 5-Substituted Benzovesamicol Analogs containing N-Substituted Amides as Potential Positron Emission Tomography Tracers for the Vesicular Acetylcholine Transporter
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2017 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 19, p. 5095-5106Article in journal (Refereed) Published
Abstract [en]

Herein, new ligands for the vesicular acetylcholine transporter (VAChT), based on a benzovesamicol scaffold, are presented. VAChT is acknowledged as a marker for cholinergic neurons and a positron emission tomography tracer for VAChT could serve as a tool for quantitative analysis of cholinergic neuronal density. With an easily accessible triflate precursor, aminocarbonylations were utilized to evaluate the chemical space around the C5 position on the tetrahydronaphthol ring. Synthesized ligands were evaluated for their affinity and selectivity for VAChT. Small, preferably aromatic, N-substituents proved to be more potent than larger substituents. Of the fifteen compounds synthesized, benzyl derivatives (+/-)-7i and (+/-)-7l had the highest affinities for VAChT. Compound (+/-)-7i was chosen to investigate the importance of stereochemistry for binding to VAChT and selectivity toward the sigma(1) and sigma(2) receptors. Enantiomeric resolution gave (+/-)-7i and (-)-7i, and the eutomer showed seven times better affinity. Although racemate (+/-)-7i was initially promising, the affinity of (-)-7i for VAChT was not better than 56.7 nM which precludes further preclinical evaluation. However, the nanomolar binding together with the ready synthesis of [C-11]-(+/-)-7i shows that (-)-7i can serve as a scaffold for future optimizations to provide improved C-11-labelled VAChT PET tracers.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-332288 (URN)10.1016/j.bmc.2017.01.041 (DOI)000413401200010 ()28185725 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2017-10-26 Created: 2017-10-26 Last updated: 2018-09-14Bibliographically approved
3. Palladium and Visible-Light Mediated Carbonylative Suzuki-Miyaura Coupling of Unactivated Alkyl Halides and Aryl Boronic Acids
Open this publication in new window or tab >>Palladium and Visible-Light Mediated Carbonylative Suzuki-Miyaura Coupling of Unactivated Alkyl Halides and Aryl Boronic Acids
2017 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 53, p. 6895-6898Article in journal (Refereed) Published
Abstract [en]

Herein, a simple and efficient method for the palladium-catalyzed carbonylation of aryl boronic acids with unactivated alkyl iodides and bromides under visible-light irradiation, ambient temperature and low CO-pressure is presented. Notably, the procedure uses readily available equipment and an inexpensive palladium catalyst to generate the key alkyl radical intermediate. These mild conditions enabled the synthesis of a range of functionalized aryl alkyl ketones including the antipsychotic drug, melperone.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2017
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-329634 (URN)10.1039/c7cc02763j (DOI)000404282900021 ()
Available from: 2017-09-26 Created: 2017-09-26 Last updated: 2017-10-26
4. Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation
Open this publication in new window or tab >>Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation
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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.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-332289 (URN)10.3390/molecules22101688 (DOI)000414670600115 ()
Available from: 2017-10-26 Created: 2017-10-26 Last updated: 2018-03-12Bibliographically approved
5. Acylamidines by Pd-Catalyzed Aminocarbonylation: One-Pot Cyclizations and 11C-Labeling
Open this publication in new window or tab >>Acylamidines by Pd-Catalyzed Aminocarbonylation: One-Pot Cyclizations and 11C-Labeling
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(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-332292 (URN)
Available from: 2017-10-26 Created: 2017-10-26 Last updated: 2017-10-26

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