| Autor: |
Brust, P., Deuther-Conrad, W., Becker, G., Patt, M., Dont, C. K., Stittsworth, S., Fischer, S., Hiller, A., Wenzel, B., Dukic-Stefanovic, S., Hesse, S., Steinbach, J., Wünsch, B., Lever, S. Z., Sabri, O. |
| Jazyk: |
angličtina |
| Rok vydání: |
2014 |
| Zdroj: |
Journal of Nuclear Medicine 55(2014)10, 1730-1736 |
| Popis: |
Because of their involvement in growth and survival signaling cascades, the sigma1 receptors (σ1Rs) represent a novel target for the treatment of cancer and several brain diseases such as depression and neurodegeneration. From a series of σ1R-specific 18F-fluoroalkylated spirocyclic piperidines, we have chosen 18F-fluspidine for detailed investigation of the in vivo kinetics of the (R)-(+)- and (S)-(-)-enantiomers to identify their potential for imaging in humans. Methods: Enantiopure tosylate precursors for radiolabeling were obtained using chiral preparative high-performance liquid chromatography and used for radiosynthesis of both 18F-fluspidine enantiomers by nucleophilic substitution with K-18F-F-Kryptofix 222-carbonate complex in a synthesis module. Brain pharmacokinetics were investigated by dynamic PET studies in piglets under baseline and blocking conditions using the highly selective σ1R agonist SA4503. Standardized uptake values (SUVs) were calculated for 24 MR-defined brain regions. Total distribution volume (VT) and binding potentials (k3'/k4T98% and >96% enantiomeric excess, respectively). (S)-(-)- and (R)-(+)-18F-fluspidine were synthesized within approximately 70 min (radiochemical yield, 35%-45%; specific activity, 650-870 GBq/µmol; radiochemical purity, >99%). Both radiotracers displayed different brain uptake kinetics. Although the initial brain uptake was similar, the SUV at the end of the study differed significantly (P18F-fluspidine showing about 60%-150% higher values. Administration of SA4503 reduced SUV almost equally for both radiotracers by approximately 65%. Furthermore, k3' was significantly decreased under blocking conditions in almost all regions ((S)-(-)-18F-fluspidine, -90%-95%; (R)-(+)-18F-fluspidine, -70%-90%) wereas effects on k4 differd according to the particular brain region. VT estimated by both graphical analysis using Logan plots and full nonlinear kinetic analysis revealed significant inhibition for both radiotracers under blocking conditions. Conclusion: Both (S)-(-)-18F-fluspidine and (R)-(+)-18F-fluspidine appear to be suitable for σ1R imaging in humans. The different pharmacokinetics of (S)-(-)-18F-fluspidine and (R)-(+)-18F-fluspidine may have the potential for application in the diagnostics of different pathologic conditions. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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