Evaluation of 18F-labeled benzodioxine piperazine-based dopamine D4 receptor ligands: Lipophilicity as a determinate of nonspecific binding
Kügler F, Sihver W, Ermert J, Hübner H, Gmeiner P, Prante O, Coenen HH (2011)
Publication Language: English
Publication Type: Journal article, Original article
Publication year: 2011
Journal
Original Authors: Kugler F., Sihver W., Ermert J., Hubner H., Gmeiner P., Prante O., Coenen H.H.
Publisher: American Chemical Society
Book Volume: 54
Pages Range: 8343-8352
Journal Issue: 24
DOI: 10.1021/jm200762g
Abstract
Derivatization of the putative neuroleptic 1-(2,3-dihydrobenzo[1,4]dioxin- 6-yl)-4-(4-fluorobenzyl)-piperazine (3a) led to a series of new dopamine receptor D ligands displaying high affinity (K = 1.1-15 nM) and D /D subtype selectivities of about 800-6700. These ligands were labeled with the short-lived positron emitter fluorine-18 and analyzed for their potential application for imaging studies by positron emission tomography (PET). In vitro autoradio-graphy was used to determine their nonspecific binding behavior as a result of their structural and thus physicochem-ical properties. The biodistribution, in vivo stability, and brain uptake of the most promising D radioligand candidate were determined. This proved to be 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-((6- fluoropyridin-3-yl)methyl)piperazine ([ F]3d), which revealed an excellent binding pattern with a high selectivity and limited nonspecific binding in vitro. This analogue also exhibited a high stability and an extremely high brain uptake in vivo with specific binding in hippocampus, cortex, colliculus, and cerebellum as determined by ex vivo autoradiography. Thus, [ F]3d appears as a suitable D radioligand for in vivo imaging, encouraging continued evaluation by PET studies. (Figure presented) © 2011 American Chemical Society.
Authors with CRIS profile
Harald Hübner
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Olaf Prante
Professur für Molekulare Bildgebung und Radiochemie
Additional Organisation(s)
Involved external institutions
Germany (DE)How to cite
APA:
Kügler, F., Sihver, W., Ermert, J., Hübner, H., Gmeiner, P., Prante, O., & Coenen, H.H. (2011). Evaluation of 18F-labeled benzodioxine piperazine-based dopamine D4 receptor ligands: Lipophilicity as a determinate of nonspecific binding. Journal of Medicinal Chemistry, 54(24), 8343-8352. https://doi.org/10.1021/jm200762g
MLA:
Kügler, Fabian, et al. "Evaluation of 18F-labeled benzodioxine piperazine-based dopamine D4 receptor ligands: Lipophilicity as a determinate of nonspecific binding." Journal of Medicinal Chemistry 54.24 (2011): 8343-8352.
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