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Synthesis of the Aryl Iodide Precursor of [Carboxyl-11C]Candesartan
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
Uppsala Imanet, GE Healthcare.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
(Engelska)Manuskript (Övrigt vetenskapligt)
Nationell ämneskategori
Organisk kemi
Forskningsämne
Oorganisk kemi; Organisk farmaceutisk kemi
Identifikatorer
URN: urn:nbn:se:uu:diva-98597OAI: oai:DiVA.org:uu-98597DiVA, id: diva2:201505
Tillgänglig från: 2009-03-04 Skapad: 2009-02-27 Senast uppdaterad: 2013-10-02
Ingår i avhandling
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
Öppna denna publikation i ny flik eller fönster >>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 (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
[11C]carbon monoxide, isotopic labelling, PET, acrylamide, EGFR, VEGFR-2, 11C
Nationell ämneskategori
Organisk kemi
Forskningsämne
Organisk kemi; Organisk farmaceutisk kemi
Identifikatorer
urn:nbn:se:uu:diva-98599 (URN)978-91-554-7451-5 (ISBN)
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

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Åberg, OlaLångström, Bengt

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