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Synthesis and Biological Evaluation of [Carboxyl-11C]eprosartan
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala Imanet, GE Healhcare.
Uppsala ASL, GE .
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
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2009 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 52, no 8, 295-303 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2009. Vol. 52, no 8, 295-303 p.
Keyword [en]
angiotensin II, AT1, eprosartan, [11C]carbon monoxide, carboxylation, isotopic labelling, 11C, PET
National Category
Organic Chemistry
Research subject
Organic Pharmaceutical Chemistry; Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-98594DOI: 10.1002/jlcr.1598ISI: 000268690300032OAI: oai:DiVA.org:uu-98594DiVA: diva2:175156
Available from: 2009-02-27 Created: 2009-02-27 Last updated: 2013-03-15Bibliographically approved
In thesis
1. 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
Open this publication in new window or tab >>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
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 616
Keyword
[11C]carbon monoxide, isotopic labelling, PET, acrylamide, EGFR, VEGFR-2, 11C
National Category
Organic Chemistry
Research subject
Organic Chemistry; Organic Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-98599 (URN)978-91-554-7451-5 (ISBN)
Public defence
2009-04-17, BMC, B42, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-03-26 Created: 2009-02-27 Last updated: 2012-08-03Bibliographically approved

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Åberg, OlaHellman, PerBengt, Långström

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