Development of Radiotracers for Imaging of Sigma1 Receptors in the Human Brain
Final Report Abstract
It is widely accepted that sigma (s) receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. Among the two different s-receptor types, the s1 receptors are expected to be of major impact. Investigations of brain s1 receptors with positron emission tomography (PET) may provide a significant contribution to the understanding of the cross-talk between s1 receptors and brain neurotransmitter systems. The new insights into these functional interrelationship allow a better diagnosis of brain diseases and the development of new therapeutic concepts. At present no radiotracers for PET are available which are optimal for clinical application. Among many different structural classes of s1 receptor ligands, the spiropiperidines which were recently developed by one of the applicants of this proposal offer the best potential regarding receptor affinity and selectivity towards s2 and other brain receptors. Based on this previous work new fluorinated derivatives were synthesized in this project and characterized regarding their receptor-binding properties. Compounds with highest affinities and best selectivities were chosen for radiolabelling with 18F. Suitable precursors were synthesized for this purpose and labelling procedures for three different compounds were developed. Only one of them proved to be suitable for further investigation in vivo. Animal experiments were performed to investigate the biodistribution and the receptor binding in vivo of the related radiotracer. We found a good brain uptake and specific radiotracer accumulation in s1 receptor containing organs. However there is evidence that some degradation of the radiotracer occurs in vivo. In conclusion, based on spiropiperidine derivatives, we have developed radiotracers which have a high affinity and selectivity for s1 receptors. The potential of one radiotracer for neuroimaging with PET was evaluated by animal experiments. Although promising results were obtained further chemical derivatization is needed to optimize the biological properties of the radiotracer.
Publications
- (2006) Synthesis and pharmacological characterization of sila-panamesine, a sila-analogue of the s receptor ligand panamesine (EMD 57445). Organometallics 25, 5396-5408
R. Ilg, C. Burschka, B. Wünsch, D. Schepmann, R. Tacke
- (2007) Synthesis of bicyclic sigma receptor ligands with cytotoxic activity. J Med Chem. 50: 6144-53
C. Geiger, C. Zelenka, M. Weigl, R. Fröhlich, B. Wibbeling, K. Lehmkuhl, D. Schepmann, R. Grünert, P. J. Bednarski, B. Wünsch
- (2007) Synthesis of bridged piperazines with sigma receptor affinity. Eur J Med Chem. 42:1247-62
M. Weigl, B. Wünsch
- (2008) Development of spirocyclic s1-receptor-ligands for PET studies. 46. Jahrestagung der Deutschen Gesellschaft für Nuklearmedizin, Leipzig 23. – 26.4. 2008
Große Maestrup, E., Fischer, S., Hiller, A., Scheunemann, M., Brust, P., Steinbach, J., Wünsch, B.
- (2008) Sigma Receptors as Targets for Novel CNS and Antitumor Agents. 18. Arbeitstagung der AG Radiochemie / Radiopharmazie der DGN, Münster, 27.9.2008
Wünsch, B.
- (2008) Sila-haloperidol: a new synthesis using the 2,4,6-trimethoxyphenyl unit as a protecting group and additional pharmacological data. Chem. Med. Chem. 3, 152-164
F. Popp, B. Müller, C. Burschka, R. Bertermann, A. Hamacher, M. U. Kassack, D. Schepmann, B. Wünsch, R. Tacke
- (2008) Synthese spirocyclischer s1-Rezeptor-Liganden für PET-Untersuchungen. Jahrestagung der Deutschen Pharmazeutischen Gesellschaft, Bonn, 8. – 10.10. 2008
Große Maestrup, E.; Schepmann, D.; Wünsch, B.
- (2008) Synthesis and structure-affinity relationships of novel spirocyclic s receptor ligands with furopyrazole structure. Bioorg Med Chem. 16:2992-3001
T. Schläger, D. Schepmann, E. U. Würthwein, B. Wünsch
- (2008) Thiophene bioisosteres of spirocyclic s receptor ligands. 1. N-substituted spiro[piperidine-4,4'-thieno[3,2-c]pyrans]. J Med Chem. 51:6531-7
C. Oberdorf, D. Schepmann, L.M. Vela, J.L. Diaz, J. Holenz, B. Wünsch
- (2009) 1,4-Diazepanes derived from (S)-serine - Homopiperazines with improved s1 receptor affinity and selectivity. Eur J Med Chem.
S. Bedürftig, B. Wünsch
(See online at https://doi.org/10.1016/j.ejmech.2008.03.033) - (2009) 47. Jahrestagung der Deutschen Gesellschaft für Nuklearmedizin, Leipzig 22. - 25.4. 2009
Große Maestrup, E., Fischer, S., Hiller, A., Scheunemann, M., Brust, P., Steinbach, J., Wünsch, B.
- (2009) F- 18 markierte Radiotracer für das molekulare Imaging von s1-Rezeptoren im Hirn. 47. Jahrestagung der Deutschen Gesellschaft für Nuklearmedizin, Leipzig 22. - 25.4. 2009
Fischer, S., Große Maestrup, E., Hiller, A., Deuther-Conrad, W., Wünsch, B. Steinbach, J., Brust, P.
- (2009). 18F labelled spirocyclic ligands for molecular imaging of s1 receptor in brain. 18th Int. Symp. on Radiopharm. Sciences, Edmonton (Canada), 12 - 17 July
Fischer, S., Große Maestrup, E., Hiller, A., Deuther-Conrad, W., Schepmann, D., Wünsch, B., Steinbach, J., Brust, P.
