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Design and Synthesis of 11C-Labelled Compound Libraries for the Molecular Imaging of EGFr, VEGFr-2, AT1 and AT2 Receptors: Transition-Metal Mediated Carbonylations Using [11C]Carbon Monoxide
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

This work deals with radiochemistry and new approaches to develop novel PET tracers labelled with the radionuclide 11C.

Two methods for the synthesis of 11C-labelled acrylamides have been explored. First, [1-11C]-acrylic acid was obtained from a palladium(0)-mediated 11C-carboxylation of acetylene with [11C]carbon monoxide; this could be converted to the corresponding acyl chloride and then combined with benzylamine to form N-benzyl[carbonyl-11C]acrylamide. In the second method, the palladium(0)-mediated carbonylation of vinyl halides with [11C]carbon monoxide was explored. This latter method, yielded labelled acrylamides in a single step with retention of configuration at the C=C double bond, and required less amine compared to the acetylene method.

The vinyl halide method was used to synthesize a library of 11C-labelled EGFr-inhibitors in 7-61% decay corrected radiochemical yield via a combinatorial approach. The compounds were designed to target either the active or the inactive form of EGFr, following computational docking studies.

The rhodium(I)-mediated carbonylative cross-coupling of an azide and an amine was shown to be a very general reaction and was used to synthesize a library of dual VEGFr-2/PDGFrβ inhibitors that were 11C-labelled at the urea position in 38-78% dc rcy.

The angiotensin II AT1 receptor antagonist eprosartan was 11C-labelled at one of the carboxyl groups in one step using a palladium(0)-mediated carboxylation. Autoradiography shows specific binding in rat kidney, lung and adrenal cortex, and organ distribution shows a high accumulation in the intestines, kidneys and liver. Specific binding in frozen sections of human adrenal incidentalomas warrants further investigations of this tracer.

Three angiotensin II AT2 ligands were 11C-labelled at the amide group in a palladium(0)-mediated aminocarbonylation in 16-36% dc rcy. One of the compounds was evaluated using in vitro using autoradiography, and in vivo using organ distribution and animal PET. The compound was metabolized fast and excreted via urine. High radioactivity was also found in the liver, meaning that more metabolically stable compounds are desirable for future development.

 

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis , 2009. , s. 65
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 616
Nyckelord [en]
[11C]carbon monoxide, isotopic labelling, PET, acrylamide, EGFR, VEGFR-2, 11C
Nationell ämneskategori
Organisk kemi
Forskningsämne
Organisk kemi; Organisk farmaceutisk kemi
Identifikatorer
URN: urn:nbn:se:uu:diva-98599ISBN: 978-91-554-7451-5 (tryckt)OAI: oai:DiVA.org:uu-98599DiVA, id: diva2:207365
Disputation
2009-04-17, BMC, B42, Husargatan 3, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-03-26 Skapad: 2009-02-27 Senast uppdaterad: 2012-08-03Bibliografiskt granskad
Delarbeten
1. Synthesis of [11C]/[13C]acrylamides by palladium-mediated carbonylation
Öppna denna publikation i ny flik eller fönster >>Synthesis of [11C]/[13C]acrylamides by palladium-mediated carbonylation
2007 (Engelska)Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 3, s. 455-461Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Two methods are presented for the synthesis of acrylamides labelled with C-11 (beta(+), t(1/2) = 20.4 min) and C-11 in the carbonyl position. In the first method, [1-C-11]acrylic acid is synthesised from [C-11]carbon monoxide by palladium-mediated hydroxy-carbonylation of acetylene. The labelled carboxylic acid is converted into the acyl chloride and subsequently treated with amine to yield N-benzyl[carbonyl(11)C]acrylamide, The second method utilizes [C-11]carbon monoxide in a palladium-mediated carbonylative cross-coupling of vinyl halides and amines. A higher radiochemical yield is achieved with the latter method and the amount of amine needed is decreased to 1/20. The C-11-labelled acrylamides were isolated in up to 81 % decay-corrected radiochemical yield. Starting from 10 +/- 0.5GBq of [C-11]carbon monoxide, N-benzyl[carbonyl-C-11]acrylamide was obtained in 4 min with a specific radioactivity of 330 +/- 4 GBq mu mol-(1). Co-labelling with C-11 and C-13 enabled confirmation of the labelled position by C-13 NMR spectroscopy.

Nyckelord
Carbonylation, Amides, Carbon monoxide, Isotopic labelling, Carbon-11, 11C, PET
Nationell ämneskategori
Kemi
Forskningsämne
Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-98592 (URN)10.1002/ejoc.200600700 (DOI)000243600100007 ()
Tillgänglig från: 2009-02-27 Skapad: 2009-02-27 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
2. Synthesis of a Library of 11C-Carbonyl-labelled Irreversibly Binding EGFr Inhibitors as Potential Biomarkers for Tumours
Öppna denna publikation i ny flik eller fönster >>Synthesis of a Library of 11C-Carbonyl-labelled Irreversibly Binding EGFr Inhibitors as Potential Biomarkers for Tumours
(Engelska)Manuskript (Övrigt vetenskapligt)
Nyckelord
[11C]carbon monoxide, isotopic labelling, EGFR, molecular imaging, PET, kinase, acrylamide
Nationell ämneskategori
Organisk kemi
Forskningsämne
Organisk kemi; Organisk farmaceutisk kemi
Identifikatorer
urn:nbn:se:uu:diva-98596 (URN)
Tillgänglig från: 2009-03-04 Skapad: 2009-02-27 Senast uppdaterad: 2013-10-02
3. Rhodium-mediated [11C]Carbonylation: A library of N-phenyl-N′-{4-(4-quinolyloxy)-phenyl}-[11C]-urea derivatives as potential PET angiogenic probes
Öppna denna publikation i ny flik eller fönster >>Rhodium-mediated [11C]Carbonylation: A library of N-phenyl-N′-{4-(4-quinolyloxy)-phenyl}-[11C]-urea derivatives as potential PET angiogenic probes
2009 (Engelska)Ingår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 52, nr 5, s. 151-157Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

As part of our ongoing investigation into the imaging of angiogenic processes, a small library of eight vascular endothelial growth factor receptor-2 (VEGFR-2)/platelet-derived growth factor receptor beta dual inhibitors based on the N-phenyl-N'-4-(4-quinolyloxy)-phenyl-urea was labelled with C-11 (beta(+), t(1/2) = 20.4 min) in the urea carbonyl position via rhodium-mediated carbonylative cross-coupling of an aryl azide and different anilines. The decay-corrected radiochemical yields of the isolated products were in the range of 38-81% calculated from [C-11]carbon monoxide. Starting with 10.7+/-0.5 GBq of [C-11]carbon monoxide, 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-fluoro-phenyl)-[C-11]-urea (2.1 GBq) was isolated after total reaction time of 45 min with a specific activity of 92+/-4 GBq mu mol(-1).

Nyckelord
carbonylation, carbon-11, 11C, angiogenesis, VEGFR-2, PET, kinase
Nationell ämneskategori
Organisk kemi
Forskningsämne
Organisk kemi; Organisk farmaceutisk kemi
Identifikatorer
urn:nbn:se:uu:diva-98593 (URN)10.1002/jlcr.1582 (DOI)000267243600003 ()
Tillgänglig från: 2009-02-27 Skapad: 2009-02-27 Senast uppdaterad: 2017-12-13
4. Synthesis of Asymmetric [11C]Ureas and [11C]Sulphonylureas by Rh(I)-Mediated Carbonylation
Öppna denna publikation i ny flik eller fönster >>Synthesis of Asymmetric [11C]Ureas and [11C]Sulphonylureas by Rh(I)-Mediated Carbonylation
(Engelska)Manuskript (Övrigt vetenskapligt)
Nyckelord
[11C]carbon monoxide, urea, sulfonurea, tolbutamide, isotopic labelling, 11C, carbon-11
Nationell ämneskategori
Organisk kemi
Forskningsämne
Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-98598 (URN)
Tillgänglig från: 2009-03-05 Skapad: 2009-02-27 Senast uppdaterad: 2013-10-02
5. Synthesis and Biological Evaluation of [Carboxyl-11C]eprosartan
Öppna denna publikation i ny flik eller fönster >>Synthesis and Biological Evaluation of [Carboxyl-11C]eprosartan
Visa övriga...
2009 (Engelska)Ingår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 52, nr 8, s. 295-303Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Essential hypertension occurs in approximately 25% of the adult population and one cause of hypertension is primary aldosteronism. Targeting the angiotensin II AT1 receptor using PET and an appropriate tracer may offer a diagnostic method for adrenocortical tissue. This report describes the synthesis of the selective AT1 receptor antagonist [carboxyl-11C]eprosartan 10, 4-[2-butyl-5-((E)-2-carboxy-3-thiophen-2-yl-propenyl)-imidazol-1-ylmethyl]-[carboxyl-11C]benzoic acid, and its precursor (E)-3-[2-butyl-3-(4-iodo-benzyl)-3H-imidazol-4-yl]-2-thiophen-2-ylmethyl-acrylic acid 9. 11C-carboxylation of the iodobenzyl moiety was performed using a palladium-mediated reaction with [11C]carbon monoxide in the presence of tetra-n-butyl-ammonium hydroxide in a micro-autoclave using a temperature gradient from 25 to 140°C over 5 min. After purification by semipreparative HPLC, [carboxyl-11C]eprosartan 10 was obtained in 37–54% decay-corrected radiochemical yield (from [11C]carbon monoxide) with a radiochemical purity >95% within 35 min of the end of bombardment (EOB). A 5-µAh bombardment gave 2.04 GBq of 10 (50% rcy from [11C]carbon monoxide) with a specific activity of 160 GBq µmol−1 at 34 min after EOB. Frozen-section autoradiography shows specific binding in kidney, lung and adrenal cortex. In vivo experiments in rats demonstrate a high accumulation in kidney, liver and intestinal wall.

Nyckelord
angiotensin II, AT1, eprosartan, [11C]carbon monoxide, carboxylation, isotopic labelling, 11C, PET
Nationell ämneskategori
Organisk kemi
Forskningsämne
Organisk farmaceutisk kemi; Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-98594 (URN)10.1002/jlcr.1598 (DOI)000268690300032 ()
Tillgänglig från: 2009-02-27 Skapad: 2009-02-27 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
6. Synthesis and evaluation of a 11C-labelled angiotensin II AT2 receptor ligand
Öppna denna publikation i ny flik eller fönster >>Synthesis and evaluation of a 11C-labelled angiotensin II AT2 receptor ligand
Visa övriga...
2010 (Engelska)Ingår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 53, nr 10, s. 616-624Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Three C-11-radiolabelled high-affinity nonpeptide AT(2) receptor-selective ligands were synthesized and one of these was evaluated as positron emission tomography (PET) tracer. The labelling reaction was performed via palladium(0)-mediated aminocarbonylation of the aryl iodide substrate using [C-11] carbon monoxide as the labelled precursor. As an example, starting with 10.0 GBq [C-11] carbon monoxide, 1.10 GBq of the product N-butoxycarbonyl-3-[4-(N-benzyl-[C-11] carbamoyl)phenyl]-5-isobutylthiophene-2-sulphonamide [C-11]4d was obtained in 36% decay-corrected radiochemical yield (from [C-11] carbon monoxide), 42 min from end of bombardment with a specific activity of 110 GBq.mu mol(-1). The N-isopropyl-[C-11] carbamoyl-analogue [C-11]4c (radiochemical purity >95%) was studied employing autoradiography, organ distribution, and small animal PET. In vitro autoradiography showed specific binding in the pancreas and kidney. Organ distribution in six rats revealed a high uptake in the liver, intestine, kidney, and adrenals. Small animal PET showed rapid and reversible uptake in the kidneys followed by accumulation in the urinary bladder suggesting fast renal excretion of the tracer. In addition, high accumulation was also seen in the liver. For future studies, more metabolically stable tracers will need to be developed. To the best of our knowledge, this is the first attempt of the use of PET imaging for the detection of expressed, fully functional AT(2) receptors in living subjects.

Nyckelord
angiotensin II, AT2, PET, 11C, aminocarbonylation, [11C]carbon monoxide
Nationell ämneskategori
Organisk kemi
Forskningsämne
Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-98914 (URN)10.1002/jlcr.1793 (DOI)000282667600004 ()
Tillgänglig från: 2009-03-05 Skapad: 2009-03-05 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
7. Synthesis of the Aryl Iodide Precursor of [Carboxyl-11C]Candesartan
Öppna denna publikation i ny flik eller fönster >>Synthesis of the Aryl Iodide Precursor of [Carboxyl-11C]Candesartan
(Engelska)Manuskript (Övrigt vetenskapligt)
Nationell ämneskategori
Organisk kemi
Forskningsämne
Oorganisk kemi; Organisk farmaceutisk kemi
Identifikatorer
urn:nbn:se:uu:diva-98597 (URN)
Tillgänglig från: 2009-03-04 Skapad: 2009-02-27 Senast uppdaterad: 2013-10-02

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