167273-56-5Relevant articles and documents
Radiosynthesis and evaluation of 18F-labeled dopamine D4-receptor ligands
Willmann, Michael,Ermert, Johannes,Prante, Olaf,Hübner, Harald,Gmeiner, Peter,Neumaier, Bernd
, p. 43 - 52 (2020/08/03)
Introduction: The dopamine D4 receptor (D4R) has attracted considerable attention as potential target for the treatment of a broad range of central nervous system disorders. Although many efforts have been made to improve the performance of putative radioligand candidates, there is still a lack of D4R selective tracers suitable for in vivo PET imaging. Thus, the objective of this work was to develop a D4-selective PET ligand for clinical applications. Methods: Four compounds based on previous and new lead structures were prepared and characterized with regard to their D4R subtype selectivity and predicted lipophilicity. From these, 3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridine I and (S)-4-(3-fluoro-4-methoxybenzyl)-2-(phenoxymethyl)morpholine II were selected for labeling with fluorine-18 and subsequent evaluation by in vitro autoradiography to assess their suitability as D4 radioligand candidates for in vivo imaging. Results: The radiosynthesis of [18F]I and [18F]II was successfully achieved by copper-mediated radiofluorination with radiochemical yields of 7% and 66%, respectively. The radioligand [18F]II showed specific binding in areas where D4 expression is expected, whereas [18F]I did not show any uptake in distinct brain regions and exhibited an unacceptable degree of non-specific binding. Conclusions: The compounds studied exhibited high D4R subtype selectivity and logP values compatible with high brain uptake, but only ligand [18F]II showed low non-specific binding and is therefore a good candidate for further evaluation. Advances in knowledge: The discovery of new lead structures for high-affinity D4 ligands opens up new possibilities for the development of suitable PET-radioligands. Implications for patient: PET-imaging of dopamine D4-receptors could facilitate understanding, diagnosis and treatment of neuropsychiatric and neurodegenerative diseases.
Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists
Witt, Jonathan O.,McCollum, Andrea L.,Hurtado, Miguel A.,Huseman, Eric D.,Jeffries, Daniel E.,Temple, Kayla J.,Plumley, Hyekyung C.,Blobaum, Anna L.,Lindsley, Craig W.,Hopkins, Corey R.
, p. 2481 - 2488 (2016/07/07)
Herein, we report the synthesis and structure-activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl)oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (1, D2L, D2S, D3, and D5).
2-Aryloxymethylmorpholine histamine H3 antagonists
Letavic, Michael A.,Keith, John M.,Ly, Kiev S.,Bonaventure, Pascal,Feinstein, Mark A.,Lord, Brian,Miller, Kirsten L.,Motley, S. Timothy,Nepomuceno, Diane,Sutton, Steven W.,Carruthers, Nicholas I.
scheme or table, p. 5796 - 5799 (2009/11/30)
The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H3 antagonists is described. The new compounds are high affinity histamine H3 ligands that penetrate the CNS and occupy the histamine H3 receptor in rat brain.
