252364-41-3Relevant academic research and scientific papers
Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT2A/mGlu2Receptor Complex
Poulie, Christian B. M.,Liu, Na,Jensen, Anders A.,Bunch, Lennart
, p. 9928 - 9949 (2020/09/12)
We report the synthesis of the first series of heterobivalent ligands targeting the putative heteromeric 5-HT2A/mGlu2 receptor complex, based on the 5-HT2A antagonist MDL-100,907 and the mGlu2 ago-PAM JNJ-42491293. The functional properties of monovalent and heterobivalent ligands were characterized in 5-HT2A-, mGlu2/Gqo5-, 5-HT2A/mGlu2-, and 5-HT2A/mGlu2/Gqo5-expressing HEK293 cells using a Ca2+ imaging assay and a [3H]ketanserin binding assay. Pronounced functional crosstalk was observed between the two receptors in 5-HT2A/mGlu2 and 5-HT2A/mGlu2/Gqo5 cells. While the synthesized monovalent ligands retained the 5-HT2A antagonist and mGlu2 ago-PAM functionalities, the seven bivalent ligands inhibited 5-HT-induced responses in 5-HT2A/mGlu2 cells and both 5-HT- and Glu-induced responses in 5-HT2A/mGlu2/Gqo5 cells. However, no definitive correlation between the functional potency and spacer length of the ligands was observed, an observation substantiated by the binding affinities exhibited by the compounds in 5-HT2A, 5-HT2A/mGlu2, and 5-HT2A/mGlu2/Gqo5 cells. In conclusion, while functional crosstalk between 5-HT2A and mGlu2 was demonstrated, it remains unclear how these heterobivalent ligands interact with the putative receptor complex.
Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET
Herth, Matthias M.,Kramer, Vasko,Piel, Markus,Palner, Mikael,Riss, Patrick J.,Knudsen, Gitte M.,Roesch, Frank
experimental part, p. 2989 - 3002 (2009/09/05)
Radiolabelled piperidine derivatives such as [11C]MDL 100907 and [18F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with 18F-fluorine, were synthesized to improve molecular imaging properties of [11C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show Ki-values in the nanomolar range towards the 5-HT2A receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic 18F-tracers for visualization of the 5-HT2A receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have Ki values between 30 and 120 nM. All promising compounds show log P values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of 18F-labelled analogues for 5-HT2A imaging with PET.
Total synthesis and evaluation of [18F]MHMZ
Herth, Matthias M.,Debus, Fabian,Piel, Markus,Palner, Mikael,Knudsen, Gitte M.,Lueddens, Hartmut,Roesch, Frank
, p. 1515 - 1519 (2008/09/21)
Radiochemical labeling of MDL 105725 using the secondary labeling precursor 2-[18F]fluoroethyltosylate ([18F]FETos) was carried out in yields of ～90% synthesizing [18F]MHMZ in a specific activity of ～50 MBq/nmol with a sta
An efficient synthesis of the precursors of [11C]MDL 100907 labeled in two specific positions
Huang, Yiyun,Mahmood, Khalid,Mathis, Chester A.
, p. 949 - 957 (2007/10/03)
An efficient, integrated route for the synthesis of two precursors of [11C]MDL 100907 labeled in the 2'- or 3'-methoxy position is reported. The synthesis involved a one-pot, two-step process to transform the intermediate esters to ketones and subsequent resolution of the racemic alcohols to their respective enantiomers. The resolved, enantiomerically pure phenol precursors were reacted with high specific activity [11C]methyl iodide to produce [11C]MDL 100907 labeled in two specific positions.
