TY  - THES
AU  - Hocke, Carsten
TI  - Untersuchungen zur n.c.a. 18F- und 123I-Markierung Subtyp-selektiver Derivate des 5HT1A Rezeptorliganden WAY 100635
VL  - 3895
IS  - Juel-3895
SN  - 0944-2952
PB  - Univ. Köln
VL  - Dr. (Univ.)
CY  - Jülich
M1  - PreJuSER-44139
M1  - Juel-3895
T2  - Berichte des Forschungszentrums Jülich
SP  - VI, 133 p.
PY  - 2001
N1  - Record converted from VDB: 12.11.2012
N1  - Köln, Univ., Diss., 2001
AB  - The serotonergic system with its différent receptor subtypes is one of the most important neuronal transmitter systems in the brain. It is involved in the regulation of various physiological functions and states of mind such as fear, depression and schizophrenia. The radioligand [11C]WAY-100635 ([" C]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)-cyclohexanecarboxamide) was successfully used in vivo as 5-HTIA antagonist. The aim of the study was to prepare in vivo stable 18F-analogues . New derivatization of WAY 100635 was at first performed by n.c.a. 18F-labelling in 4- position of the cyclohexyl group in a one-step reaction. With the diastereomeric model compounds cis/trans ethyl-4-tosylcyclohexanecarboxylate the dependence of various reaction parameters, like temperature, solvent and reaction time, on the radiochemical yield (RCY) was tested. The results were transfered to the WAY derivatives . The best results of n.c.a. 18Ffluorination were obtained at 100°C using DMSO as solvent . The radiochemical yield was about 25% for the cis-diastereomer and 5% for the trans-diastereomer of 4-[18F]fluoro-(N-[2- [4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl )-cyclohexanecarboxamide. Subsequently, the syntheses of stabilized sulfonamides and sulfinamides as new analogues of the 5-HTIA antagonist WAY 100635 were performed. The derivatives were radiolabelled with [18F]fluoride and [ 1231]iodide for in vivo applications; namely 4-iodo- and 4-fluoro-N-12-[4- (2-methoxyphenyl)-piperazin-1-yl)-ethyll-N-pyridin-2-yl-benzenesulfonamide as well as the corresponding sulfinamide analogues. With the activating sulfonamide substituent différent leaving groups (X = F, Cl, Br, I and N02) were investigated for no-carrier-added aromatic 18F-substitution. Again the effect of various reaction parameters, like temperature, solvent and leaving groups, on the maximum radiochemical yield was tested in model compounds. The results were transfered to the compounds of interest . The 18F-labelled sulfonamides were prepared by nucleophilic aromatic substitution in high RCY of 65% within 15 min using bromine as leaving group at 160°C and DMSO as solvent. The corresponding 18F-labelled sulfinamides were not stable under the labelling conditions tested. The formation of [123I]iodo-analogues of sulfonamides was accomplished by Cu(I)-assisted radioiodo-forbromo substitution in acetic acid with over 90% RCY. Finally, the 123I-labelled sulfinamide was prepared via electrophilic destannylation. The RCY of 4-[ 123I]iodo-N-12-[4-(2- methoxyphenyl) -piperazin- 1-yl)-ethyll-N-pyridin-2-yl-benzenesulfinamide was ca. 80% after 2 min in methanol/acetic acid at ambient temperature with chloramine-T as in-situ oxidizing agent. In vitro competition studies with the fluoro- and iodo-sulfonamides and -sulfinamides versus the highly selective 5-HTIA receptor ligand [3H]8-OH-DPAT lead to Ki values of 36 to 112 nM. First biodistribution studies in mice of [18F]fluoro-sulfonamide proved the increased in vivo stability
LB  - PUB:(DE-HGF)11 ; PUB:(DE-HGF)3
UR  - https://juser.fz-juelich.de/record/44139
ER  -