Trägerarme Synthese $^{18}$F-markierter, ausgewählter NMDA- und D4-Rezeptorliganden durch Einsatz geeigneter [18F]FluorbenzolderivateD$_{4}$[$^{18}$F]
Trägerarme Synthese $^{18}$F-markierter, ausgewählter NMDA- und D4-Rezeptorliganden durch Einsatz geeigneter [18F]FluorbenzolderivateD$_{4}$[$^{18}$F]
In this thesis new strategies were developed and evaluated for the no-carrier-added (n.c.a.) $^{18}$F-labelling of receptor ligands as radiodiagnostics for characterization of brain receptors using positron-emission-tomography (PET). Special emphasis was placed on the synthesis of n.c.a. ($\pm$)-3-(...
Saved in:
Personal Name(s): | Ludwig, Thomas (Corresponding author) |
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Contributing Institute: |
Nuklearchemie; INB-4 |
Imprint: |
Jülich
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag
2005
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Physical Description: |
IV, 121 S. |
Dissertation Note: |
Zugl.: Köln, Univ., Diss., 2001 |
Document Type: |
Report |
Series Title: |
Berichte des Forschungszentrums Jülich
4191 |
Subject (ZB): | |
Link: |
OpenAccess |
Publikationsportal JuSER |
In this thesis new strategies were developed and evaluated for the no-carrier-added (n.c.a.) $^{18}$F-labelling of receptor ligands as radiodiagnostics for characterization of brain receptors using positron-emission-tomography (PET). Special emphasis was placed on the synthesis of n.c.a. ($\pm$)-3-(4-hydroxy-4-(4- [$^{18}$F]fluorophenol)-piperidin-1-yl)chroman-4,7-diol, a ligand with high affinity for the NR2B subtype of NMDA receptors and n.c.a. (3-(4-[ $^{18}$F]fluorphenoxy)propyl)-(2-(4-tolylphenoxy)ethyl)amine ([$^{18}$F]FPTEA) a dopamine D$_{4}$ receptor ligand. In order to synthesize n.c.a. ($\pm$)-3-(4-hydroxy-4-(4-[ $^{18}$F]fluorophenol)-piperidin-1-yl)chroman-4,7-diol the $^{18}$F-fluoroarylation method via metallorganic intermediates was modified and improved. The precursor n.c.a. 1-bromo-4 [$^{18}$F]fluorobenzene was synthesized via diphenyliodonium salts and isolated by column chromatography with 30 - 40 % radiochemical yield. The preparation of 4-[${18}$Flfluorophenyllithium and 4-[$^{18}$F]fluorophenylmagnesium bromide via n.c.a. 1-bromo4[$^{18}$F]fluorobenzene was performed with added carrier (bromobenzene, tert.-butyliodide, ethylmagnesium bromide) in quantitative yields. The suitability of the organometallic $^{18}$F-fluoroarylation agents was proven with several model compounds. High radiochemical yields of 20 - 30 % were obtained also with piperidinone-derivatives. The preparation of a suitable precursor for the synthesis of the NMDA receptor ligand, however, could not be achieved by synthesis of appropriate 1,3-dioxolane protected piperidinone derivatives. Further, the synthesis of n.c.a. [$^{18}$F]fluoroaryloxy)alkylamines via n.c.a. 4-[$^{18}$F]fluorophenol was developed and evaluated. N.c.a. 4-[$^{18}$F]fluorophenol was prepared via a three-step synthesis starting from suitable substituted benzophenones using the Baeyer-Villiger reaction in radiochemical yields of about 60 % in a total synthesis time of 60 minutes. The synthesis of n.c.a. [$^{18}$F]fluoroarylethers with corresponding model compounds was optimized and lead to a radiochemical yield of 25 - 60 %, depending on the alkylhalide used. The preparation of n.c.a. 1-(3-bromopropoxy)-4-[$^{18}$F]fluorobenzene proved advantageous in comparison to direct use of4-[$^{18}$F]fluorophenol for coupling with a corresponding N-protected precursor for the synthesis of n.c.a. [$^{18}$F]FPTEA. With regard to the radiochemical yields and the loss of activity during the synthesis and isolation of n.c.a. 4-[$^{18}$F]fluorophenol and n.c.a. l-(3-bromopropoxy)-4-[$^{18}$F]fluorobenzene, [$^{18}$F]FPTEA was obtained by reaction with 2-(4-tolyloxy)ethylamine in radiochemical yields of about 25 - 30 % in ethanol or 2-butanone as solvent with a synthesis time of 30 minutes and a reaction temperature of 90 - 95 °C. Thus, the utility of a further $^{18}$F-synthon for labelling of electron rich arenes (i.e. [$^{18}$F]fluorophenolethers) with high specific activity could be documented. |