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Pharmacological characterization of 18F-labeled vorozole analogues.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine.
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. (bengt långström)
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(English)Manuscript (Other academic)
Abstract [en]

Two 18F-labeled analogues of vorozole ([18F]FVOZ and [18F]FVOO) have been developed as potential tools for the in vivo characterization of aromatase. The purpose of the project was to evaluate the pharmacological properties of these radioligands using a combination of in vitro binding and in vivo distribution studies in the rat and primate. Saturation binding studies with the radioligands in homogenates of rat ovary gave KD and Bmax values of 0.21 ± 0.1 nM and 210 ± 20 fmol/mg, respectively, for [18F]FVOZ, and 7.6 ± 1 nM and 293 ± 12 fmol/mg, respectively, for [18F]FVOO. Organ distribution studies in rats showed the highest accumulation in the adrenal glands, with standardized uptake values (SUVs) of 15 to 20, followed by ovaries and liver with SUVs of approximately 5. The SUVs in the remaining organs were between 0.5 and 1.5. There was probably some defluorination of both radioligands, as the accumulation of radioactivity in bone increased with time. The regional distribution in the brain was studied using ex vivo and in vitro autoradiography. In the brain, specific binding of both [18F]FVOZ and [18F]FVOO were found mainly in the amygdala. PET studies were performed in the Rhesus monkey, and these showed displaceable binding in the amygdala and the preoptic area of the hypothalamus. These studies suggest that [18F]FVOZ might be to be a suitable tracer for the study of aromatase in vitro and in vivo, and could be an alternative to [11C]vorozole in human PET-studies.

aromatase, autoradiography, biodistribution, PET, rat brain, vorozole
National Category
Other Basic Medicine Medical and Health Sciences
Research subject
Organic Chemistry; Medicine
URN: urn:nbn:se:uu:diva-88793OAI: oai:DiVA.org:uu-88793DiVA: diva2:159099
Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2010-01-14
In thesis
1. Imaging of Enzymes in the Steroid Biosynthetic Pathway: Synthesis of 18F-Labelled Tracers
Open this publication in new window or tab >>Imaging of Enzymes in the Steroid Biosynthetic Pathway: Synthesis of 18F-Labelled Tracers
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the synthesis and development of 18F-labelled alkyl etomidate and vorozole analogues, and their use as positron emission tomography (PET) tracers for the imaging of the steroid enzymes 11β-hydroxylase and aromatase. Two synthetic 18F-labelling approaches to the etomidate and vorozole analogues were developed, and the analogues were evaluated in some biological assays.

The two-step labelling method was used to synthesise many compounds for biological evaluation. In the first step, a 18F-labelled intermediate based on a ditosylate or a halogenated diethyl ether was synthesised and used directly in the next alkylation step. The decay-corrected (d.c.) radiochemical yield was higher compared to other known two-step labelling methods.

Once an appropriate candidate has been chosen for clinical evaluation, a one-step labelling method will be more suitable. We therefore developed a method based on precursors that had leaving groups at the end of their alkyl chains, and used these directly in the 18F-labelling synthesis. The one-step 18F-labelling synthesis required less reaction time and produced higher specific radioactivity and d.c. radiochemical yield than our two-step synthesis. With microwave heating, the reaction time was reduced to seconds and the d.c. radiochemical yield was better than that obtained with conventional heating. The one-step synthesis simplified the technical handling by allowing the tracer syntheses to be automated on the TRACERLab FXFN.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 54 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 607
National Category
Organic Chemistry
Research subject
Organic Chemistry
urn:nbn:se:uu:diva-89177 (URN)978-91-554-7424-9 (ISBN)
Public defence
2009-03-21, B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
Available from: 2009-02-26 Created: 2009-02-06 Last updated: 2013-05-30Bibliographically approved

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