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Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N-cyanobenzamide analogs of flufenamic acid and dazoxibene.

In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)-mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid-binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases.

Ort, förlag, år, upplaga, sidor
Uppsala: Uppsala universitet, 2014. , s. 76
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 183
Nyckelord [en]
Palladium, Carbonylation, Positron emission tomography, PET, Carbon-11, Fluor-18, Radiochemistry, Amyloidosis
Nyckelord [sv]
Palladium, Karbonyleringar, Positronemissionstomografi, PET, Kol-11, Fluor-18, Radiokemi, Amyloidos
Nationell ämneskategori
Farmaceutisk synteskemi Läkemedelskemi
Forskningsämne
Farmaceutisk vetenskap; Kemi med inriktning mot organisk kemi; Läkemedelskemi
Identifikatorer
URN: urn:nbn:se:uu:diva-213863ISBN: 978-91-554-8843-7 (tryckt)OAI: oai:DiVA.org:uu-213863DiVA, id: diva2:684450
Disputation
2014-02-21, B21, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-01-30 Skapad: 2014-01-05 Senast uppdaterad: 2018-01-11
Delarbeten
1. Aminocarbonylations Employing Mo(CO)(6) and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides
Öppna denna publikation i ny flik eller fönster >>Aminocarbonylations Employing Mo(CO)(6) and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides
2012 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, nr 24, s. 11393-11398Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A bridged two-vial system aminocarbonylation protocol where Mo(CO)(6) functions as an external in situ solid source of CO has been developed. For the first time both nitro group containing aryl/heteroaryl iodides and bromides gave good to excellent yields in the Mo(CO)(6)-mediated and palladium(0)-catalyzed conversion to benzamides, while the identical one-vessel protocol afforded extensive reduction of the nitro functionality. The above-mentioned bridged two-compartment protocol furnished good results with both primary amines and secondary amines and sluggish aniline nucleophiles at 65-85 °C reaction temperatures.

Nationell ämneskategori
Läkemedelskemi Naturvetenskap
Identifikatorer
urn:nbn:se:uu:diva-189519 (URN)10.1021/jo302322w (DOI)000312564900046 ()23205569 (PubMedID)
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseVetenskapsrådet
Tillgänglig från: 2013-01-02 Skapad: 2013-01-02 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
2. Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide
Öppna denna publikation i ny flik eller fönster >>Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide
2013 (Engelska)Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 54, nr 50, s. 6912-6915Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A novel and convenient protocol for the synthesis of N-cyanobenzamides starting from readily available aryl halides and cyanamide via palladium-catalyzed aminocarbonylation has been developed. The protocol utilizes Mo(CO)6 as the CO source or CO(gas) and affords the desired N-cyanobenzamides in moderate to good yields.

Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-212521 (URN)10.1016/j.tetlet.2013.10.040 (DOI)000327285300028 ()
Tillgänglig från: 2013-12-11 Skapad: 2013-12-11 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
3. Pd-mediated Carbonylative Synthesis of 11C-N-Cyanobenzamides
Öppna denna publikation i ny flik eller fönster >>Pd-mediated Carbonylative Synthesis of 11C-N-Cyanobenzamides
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Organisk kemi
Forskningsämne
Kemi med inriktning mot organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-213862 (URN)
Tillgänglig från: 2014-01-05 Skapad: 2014-01-05 Senast uppdaterad: 2014-02-06
4. Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors
Öppna denna publikation i ny flik eller fönster >>Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors
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2011 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, nr 1, s. 145-155Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and β-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC50 = 0.19 μM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.

Nyckelord
α-Benzylnorstatine, α-Phenylnorstatine, Alzheimer's disease, BACE-1 inhibitors, tert-Hydroxyl, Transition state mimic
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-109026 (URN)10.1016/j.bmc.2010.11.042 (DOI)000285724800014 ()21183353 (PubMedID)
Tillgänglig från: 2009-10-07 Skapad: 2009-10-07 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
5. 11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo
Öppna denna publikation i ny flik eller fönster >>11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo
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2014 (Engelska)Ingår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 41, nr 6, s. 536-543Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Introduction: The enzyme beta-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-p, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo. Methods: (11)[C]-N-1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-y1)-5-(N-methylmethylsulfonamido)-N-3-((R)-1-phenylethyl)isophthalamide, a p-secretase inhibitor, denoted here as [C-11]BSIIV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and [C-11]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats. Results: The halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21-26%. [C-11]BSI-IV was obtained in 29 +/- 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 +/- 155 GBq/umol at the end of synthesis with a radiochemical purity of >99%. The predinical studies showed that [C-11]BSI-IV has a rapid metabolism in rat with excretion to the small intestines. Conclusion: [C-11]BSI-IV was obtained in sufficient amount and purity to enable predinical investigation. The predinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that [C-11]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD.

Nationell ämneskategori
Organisk kemi Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-213860 (URN)10.1016/j.nucmedbio.2014.03.024 (DOI)000336946400014 ()
Tillgänglig från: 2014-01-05 Skapad: 2014-01-05 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
6. 11C and 18F Radiolabeling of Tetra and Pentathiophenes as PET-Ligands for Misfolded Protein Aggregates
Öppna denna publikation i ny flik eller fönster >>11C and 18F Radiolabeling of Tetra and Pentathiophenes as PET-Ligands for Misfolded Protein Aggregates
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Kardiologi Kirurgi Läkemedelskemi Organisk kemi
Forskningsämne
Läkemedelskemi; Kemi med inriktning mot organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-213861 (URN)
Tillgänglig från: 2014-01-05 Skapad: 2014-01-05 Senast uppdaterad: 2018-01-11

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