The nucleophilic aromatic substitution by [18 F]fluoride and its applications to the synthesis of model precursors for the multi step synthesis of the PET-tracer 6-[18 F]Fluoro-L-DOPA

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URI: http://nbn-resolving.de/urn:nbn:de:bsz:21-opus-23339
http://hdl.handle.net/10900/48928
Dokumentart: Dissertation
Date: 2006
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Sonstige - Chemie und Pharmazie
Advisor: Zeller, K.-P.
Day of Oral Examination: 2006-06-13
DDC Classifikation: 540 - Chemistry and allied sciences
Keywords: Nucleophile Substitution
Other Keywords: [18F]Fluorid , 6-[18F]Fluoro-L-DOPA , Nukleophile aromatische Substitution
6-[18F]Fluoro-L-DOPA , Nucleophilic aromatic substitution , [18F]Fluoride
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Inhaltszusammenfassung:

Anwendung der nukleophilen aromatischen Substitution mit [18 F]Fluorid an Modell-Substanzen für die Mehrstufensynthese des PET-Tracers 6-[18 F]Fluoro-L-DOPA

Abstract:

The objective of this study was to investigate the nucleophilic aromatic substitution using [18F]fluoride as nucleophile. Therefore, structures ranging from simple monosubstituted aromatic systems to complicated multi-substituted aromatic systems were tested, and several effects were studied in detail, including the following: 1. Structural effects (positions and number of groups on the ring, type of activation or deactivation, type of possible leaving groups and type of protection of OH groups). 2. Solvent effects (was studied using a variety of dipolar aprotic solvents) 3. Concentration effects (was studied using concentrations 1-50 mg/mL). 4. Temperature effects (was studied using temperatures 60-180 °C). Two types of reactions were studied. These are: 1. Fluorodenitration reactions: Ar-NO2 --> Ar-18F 2. Fluorodehalogenation reactions: Ar-X --> Ar-18F (X= F, Br, Cl) The study was divided into 3 parts. In the first part, aryl systems (including haloaryls, nitroaryls, benzaldehydes, acetophenones and benzophenones) were tested. In the second part, the focus was on optimising the conditions for the production of [18F]FDOPA precursors for path A (chapter 2). In the last part, model systems for producing [18F]FDOPA via path B (chapter 2) were tested in the nucleophilic aromatic substitution by [18F]fluoride. The RCYs obtained from some precursors were used further to calculate the rate constants and the energy of activation for this process. The main results can be summarised in the following points: 1. Fluorodenitration reactions can be used efficiently to produce nca [18F]arylfluorides. DMF is the best solvent but DMSO and DMAc can be used also. For very activated systems, acetonitrile can be used at lower temperatures. The optimum temperature range is 120-150 °C, although lower temperatures can be used for very activated systems. The optimum concentration range is 15-30 mg/mL and optimum time is 10-20 min. 2. Fluorodehalogenation (X= F) reactions can also be a good alternative for the synthesis of [18F]arylfluorides. DMF is the best solvent and most other solvents proved to be less efficient for carrying out this process. Optimum conditions being nearly the same as in fluorodenitration reactions. 3. Fluorodehalogenation (X= Br, Cl) reactions can also be used for the synthesis of nca [18F]arylfluorides when the conditions are well optimised. For this, DMF is the best solvent and most other solvents proved to be bad. Aromatic systems with electron withdrawing groups only on the ring gave yields which were nearly comparable to those from fluorodenitration reactions. However, with the increasing introduction of electron donating groups on the aromatic ring, the yield tend to be much lower compared to similar nitro systems. The RCYs were always directly proportional both to concentrations up to 50 mg/mL and temperatures as high as 180 °C. Calculations of the activation energy for the previous processes reveals low values in the range 16-62 kJ/mole for most systems but even lower values were obtained for very highly activated systems towards SNAr. These values indicate very fast reactions between the fluoride ion and the substituted nitro or halo benzene derivatives. In all cases the yields from the nitro derivatives were better than the halo derivatives. Within the halogens, the fluoro precursors gave always the highest yields.

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