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Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.ORCID-id: 0000-0002-9441-3767
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.ORCID-id: 0000-0003-0241-092X
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2016 (Engelska)Ingår i: ChemistryOpen, ISSN 2191-1363, Vol. 58, nr 3, s. 566-573Artikel i tidskrift (Refereegranskat) Accepted
Abstract [en]

Herein we describe the development of new methodologyfocusing on 11C-labelling of sulfonyl carbamates in a multicomponentreaction comprising a sulfonyl azide, an alkyl alcohol and [11C]CO. Anumber of 11C-labelled sulfonyl carbamates were synthesised andisolated, and the developed methodology was then applied in thepreparation of a biologically active molecule. The target compoundwas obtained in 18±8% isolated radiochemical yield and wasevaluated for binding properties in a tumor cell assay, as well asundergoing in vivo biodistribution and imaging studies. Thisrepresents the first successful radiolabelling of C21, a non-peptideangiotensin II receptor subtype 2 agonist currently in clinical trials.

Ort, förlag, år, upplaga, sidor
2016. Vol. 58, nr 3, s. 566-573
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:uu:diva-296406OAI: oai:DiVA.org:uu-296406DiVA, id: diva2:937990
Tillgänglig från: 2016-06-16 Skapad: 2016-06-16 Senast uppdaterad: 2017-11-28
Ingår i avhandling
1. Multicomponent Reactions in 11C/12C Chemistry: – Targeting the Angiotensin II Subtype 2 Receptor
Öppna denna publikation i ny flik eller fönster >>Multicomponent Reactions in 11C/12C Chemistry: – Targeting the Angiotensin II Subtype 2 Receptor
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Section 1 of this thesis contains an introduction to method development in organic synthesis, multicomponent reactions, sulfonyl azides, tracer development in 11C chemistry and the biological target.

Section 2 describes the use of sulfonyl azides in carbonylative chemistry. Paper I covers development of a diazotransfer protocol. In total, 30 arylsulfonyl azides were synthesised from primary sulfonamides (20–90% yield). 15N mechanistic studies were carried out and in Paper II, the products were converted into sulfonamides, sulfonylureas and sulfonyl carbamates (19–90% yield). For ureas and carbamates, a two-chamber protocol was employed to release CO from Mo(CO)6. 15N mechanistic studies showed that the sulfonamides were formed by direct displacement of azide.

Section 3 covers imaging and biological studies of the angiotensin II receptor subtype 2 (AT2R). In Paper III, 12 11C-sulfonyl carbamates were prepared in isolated radiochemical yields of 3–51% via Rh(I)-mediated carbonylation. The first non-peptide AT2R agonist, C21, was labelled (isolated RCY 24±10%, SA 34–51 GBq/µmol). C21 was tested in a prostate cancer assay, followed by biodistribution and small-animal PET studies. In Paper IV, a 11C-labelled AT2R ligand prepared via Pd(0)-mediated aminocarbonylation was used for autoradiography, biodistribution and small-animal PET studies.  

Section 4 describes the development of a multicomponent method for the synthesis of 3,4-dihydroquinazolinones (Paper V). 31 3,4-dihydroquinazolinones were synthesized via a cyclic iminium ion.  

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 93
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 219
Nyckelord
carbonylation, positron emission tomography, multicomponent reactions, AT2R, 3, 4-dihydroquinazolinone, sulfonyl azides
Nationell ämneskategori
Organisk kemi
Forskningsämne
Farmaceutisk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-295436 (URN)978-91-554-9636-4 (ISBN)
Externt samarbete:
Disputation
2016-09-23, Hall B21, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-09-02 Skapad: 2016-06-07 Senast uppdaterad: 2016-09-05

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Stevens, MarcChow, ChowEstrada, SergioEriksson, JonasAsplund, VeronikaOrlova, AnnaBogdan, MitranLarhed, MatsOdell, Luke

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