Radioligands for PET Imaging of the Serotonintransporter


Dysfunctions of serotonergic neuro- transmission – in particular of the serotonin transporter (SERT) – are correlated with neuropsychiatric disorders such as depression, obsessive-compulsive disorders and anxiety. Studies of serotonin transporter function and density using PET can provide an important contribution to understand corresponding functional relationships.As an important milestone for such studies the fluorine-18 labelled PET tracer (+)- [18F]FMe-McN5652 has been developed and characterised in preclinical as well as clinical studies, in cooperation with the Turku PET Centre, Finland and the Department of Nuclear Medicine, University of Leipzig. All results obtained so far lead to a successful clinical applicability (Hesse et al. 2012).

Representative ex vivo digital autoradiogram (right) of a coronal rat brain section at 60 min p.i. of (+)-[18F]FMe-McN5652. Uptake of radioactivity is evident in substantia nigra, a brain region of high SERT density (red highest, blue lowest uptake). Ex vivo digital autoradiogram of a coronal rat brain section at 60 min p.i. of (+)-[18F]FMe-McN5652

Despite overall very positive evaluation results of (+)-[18F]FMe-McN5652, the radioligand has the inherent disadvantage of a relatively high non-specific binding. This leads to our developments, based on new structure classes and pharmaceuticals, such as indolylalkyl-tetrahydroisoquinolines. In-house and in close cooperation with the Hadassah University in Jerusalem, various halogen-substituted derivatives were synthesised and characterised in radioligand binding experiments regarding their SERT affinity and selectivity versus other targets. Recently, the two 11C- and 18F-labelled compounds [11C]FMI and [18F]CFPI, respectively, have been investigated in vitro and in vivo. Revealing a high non-specific binding in porcine brain and mice in vivo, these radioligands are unfortunately not suitable for SERT-selective PET imaging.

SERT radioligands
Two new SERT radioligands (left) and in vitro autoradiographs (right) obtained after incubation of sagittal rat brain slices with [18F]CFPI without (A) or with coincubation with highly SERT affine and selective Citalopram (B).

Partner

  • Department of Nuclear Medicine, University of Leipzig

  • Turku PET Centre, Finland

  • Hebrew University Jerusalem, Israel

Publications

  • 1. Hesse, S.; Brust, P.; Mäding, P.; Becker, G.-A.; Seese, A.; Patt, M.; Sorger, D.; Zessin, J.; Sacher, J.; Lobsien, D.; Habermann, B.; Meyer. PM.; Füchtner, F.; Luthardt, J.; Bresch, A.; Steinbach, J. & Sabri O. Imaging of the brain serotonin transporters (SERT) with the new fluorine-18 labelled fluoromethyl-McN5652 and PET in humans. Eur. J. Nucl. Med. 2012, 39, 1001-1011.

  • 2. Funke, U.; Ben-Daniel, R.; Scheunemann, M.; Fischer, S.; Hiller, A.; Rühl, T.; Deuther-Conrad, W.; Patt, M.; Mishani, E.; Steinbach, J.; Sabri, O. & Brust, P. Synthesis and evaluation of THIQ based indoles as potential PET radioligands for imaging the serotonin transporter. J Label Compd Radiopharm 2011, 54, S284.

  • 3. Ben-Daniel, R.; Deuther-Conrad, W.; Scheunemann, M.; Steinbach, J.; Brust, P. & Mishani, E. Carbon-11 labeled indolylpropylamine analog as a new potential PET agent for imaging of the serotonin transporter. Bioorg Med Chem, 2008, 16, 6364-6370.

  • 4. Funke, U.; Fischer, S.; Hiller, A.; Scheunemann, M.; Deuther-Conrad, W.; Brust, P. & Steinbach, J. 3-(4-(6-fluoroalkoxy-3,4-dihydroisoquinoline-2(1H)-yl)cyclohexyl)- 1H-indole-5-carbonitriles for SERT imaging: chemical synthesis, evaluation in vitro and radiofluorination. Bioorg Med Chem Lett 2008, 18, 4727-4730.

  • 5. Vercouillie, J.; Deuther-Conrad, W.; Scheunemann, M.; Emond, P.; Fischer, S.; Funke, U.; Steinbach, J.; Guilloteau, D. & Brust, P. New fluoro- diphenylchalcogen derivatives to explore the serotonin transporter by PET. Bioorg Med Chem Lett, 2007, 17, 4991-4995.

  • 6. Brust, P.; Hesse, S.; Müller, U. & Szabo, Z. Neuroimaging of the Serotonin Transporter: Possibilities and Pitfalls. Curr Psychiat Rev, 2006, 2, 111-149.

  • 7. Deuther-Conrad, W.; Kretzschmar, M.; Wüst, F.; Pawelke, B.; Brust, P.; Steinbach, J. & Bergmann, R. [11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats. Nucl Med Biol,, 2006, 33, 53-63.

  • 8. P.; Zessin, J.; Cumming, P.; Bergmann, R. & Johannsen, B. Autoradiographic imaging of the serotonin transporter in the brainof rats and pigs using S-([18F]fluoromethyl)-(+)-McN5652. Eur Neuropsychopharmacol, 2003, 13, 387-397.

  • 9. Brust, P.; Hinz, R.; Kuwabara, H.; Hesse, S.; Zessin, J.; Pawelke, B.; Stephan, H.; Bergmann, R.; Steinbach, J. & Sabri, O. In vivo measurement of the serotonin transporter with (S)-([18F]fluoromethyl)-(+)-McN5652. Neuropsychopharmacology, 2003, 28, 2010-2019.

  • 10. Brust, P.; Zessin, J.; Kuwabara, H.; Pawelke, B.; Kretzschmar, M.; Hinz, R.; Bergman, J.; Eskola, O.; O.Solin; Steinbach, J. & Johannsen, B. Positron emission tomography imaging of the serotonin transporter in the pig brain using [11C](+)-McN5652 and S-([18F]fluoromethyl)-(+)-McN5652. Synapse, 2003, 47, 143-151.

  • 11. Marjamäki, P.; Zessin, J.; Eskola, O.; Grönroos, T.; Haaparanta, M.; Bergman, J.; Lehikoinen, P.; Forsback, S.; Brust, P.; Steinbach, J. & Solin, O. S-[18F]fluoromethyl-(+)-McN5652, a PET tracer for the serotonin transporter: evaluation in rats. Synapse, 2003, 47, 45-53.

  • 12. Zessin, J.; Eskola, O.; Brust, P.; Bergman, J.; Steinbach, J.; Lehikoinen, P.; Solin, O. & Johannsen, B. Synthesis of S-([18F]fluoromethyl)-(+)-McN5652 as a potential PET radioligand for the serotonin transporter. Nucl Med Biol, 2001, 28, 857-863.

  • 13. Brust, P.; Scheffel, U. & Szabo, Z. Radioligands for the study of the 5-HT transporter in vivo. IDrugs, 1999, 2, 129-145.