Stoll, T. (Corresponding author)FZJ*

2005
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag Jülich

Report No.: Juel-4167

Abstract: There is a great demand for radiotracers for the positron-emission-tomography (PET) to visualise the density of serotonin transporters (SERT) in the living brains of patients with psychiatric and neurological symptoms. They can help to understand the disturbances of the serotonergic system, to develop optimised pharmaceuticals and to support the planning of treatment and diagnosis. Due to high affinities to SERT and high selectivity towards other monoamine transporters there are several promising selective serotonin reuptake inhibitors in the class of Diphenyl(thio)ethers. As a result of slow pharmacokinetics of these compounds the $^{18}$F-labelling is more convenient due to the longer half-life of 109,6 min of the nuclide as compared to the so far described $^{11}$Clabelling for visualisation and quantification of the cerebral serotonin transporter. In this work four new compounds of this class were synthesised and for those there were no-carrier-added (n.c.a.) $^{18}$F-labellings designed. Using the recently described method for the formation of n.c.a. 4-[$^{18}$F]fluorophenol -(4-[$^{18}$F]fluorophenyloxy)-N-methylbenzylamine and 2-(4-[$^{18}$F]fluorophenyloxy)-N,N-dimethyl-benzylamine were synthesised via a catalytic n.c.a. diaryl ether coupling and a subsequent reduction using 1 M BH$_{3}$ • THF in THF. The whole synthesis including radio-HPLC purification could be accomplished in less than 2 hours with radiochemical yields of 20 ± 5 %. After optimisation of the diarylthioether synthesis the $^{18}$F-labelling precursors and standards for the formation of 2-(2-cyano-5-[$^{18}$F]fluorophenylthio)-N,N-dimethylbenzylamineand 2-(5-[$^{18}$F]fluoro-2-methylaminophenylthio)-N,N-dimethylbenzylamine were obtained. The n.c.a. $^{18}$F-labelling via $^{18}$F-for-NO$_{2}$ substitution and the subsequent reduction with 1 M BH$_{3}$ • THF in THF for the formation of these two radioligands were optimised, as well as the radio chromatographic isolation. In less than 2 hours the whole synthesis was completed and radiochemical yields of 34 ± 3 % could be obtained. For comparative studies additionally a modificated radiosynthesis of the recently described 2-(2-amino-5-[$^{18}$F]fluorophenylthio)-N,N-dimethylbenzylamine was developed, wherewith a promising selective serotonin reuptake inhibitor is available after a total synthesis time of 85 min with radiochemical yields of 60 ± 7 %. By in vitro membrane binding studies as well as the first distribution studies the binding characteristics of the newly synthesised compounds were determined, which did not recommend their use for in vivo application as radioligand.

Keyword(s): PET (positron emission tomography) ; radioisotope ; serotonin

1. Nuklearchemie (INB-4)