Syntheses and pharmacological characterization of novel thiazole derivatives as potential mGluR5 PET ligands

Bioorganic & Medicinal Chemistry
Cindy A BaumannSimon M Ametamey

Abstract

Four novel thiazole containing ABP688 derivatives were synthesized and evaluated for their binding affinity towards the metabotropic glutamate receptor subtype 5 (mGluR5). (E)-3-((2-(Fluoromethyl)thiazol-4-yl)ethynyl)cyclohex-2-enone O-methyl oxime (FTECMO), the ligand with the highest binding affinity (K(i)=5.5+/-1.1 nM), was labeled with fluorine-18. [(18)F]-FTECMO displayed optimal lipophilicity (log D(pH7.4)=1.6+/-0.2) and high stability in rat and human plasma as well as sufficient stability in rat liver microsomes. In vitro autoradiography with [(18)F]-FTECMO revealed a heterogeneous and displaceable binding in mGluR5-rich brain regions. PET imaging with [(18)F]-FTECMO in Wistar rats, however, showed low brain uptake. Uptake of radioactivity into the skull was observed suggesting in vivo defluorination. Thus, although [(18)F]-FTECMO is an excellent ligand for the detection of mGluR5 in vitro, its in vivo characteristics are not optimal for the imaging of mGluR5 in rats in vivo.

References

Jul 21, 2009·Trends in Pharmacological Sciences·Victor W Pike

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Citations

May 20, 2014·International Journal of Cardiology·Adrienne MüllerStefanie D Krämer
Aug 21, 2014·European Journal of Nuclear Medicine and Molecular Imaging·Selena Milicevic SephtonSimon M Ametamey
Jan 9, 2016·European Journal of Nuclear Medicine and Molecular Imaging·Rajapillai L I Pillai, Dnyanesh N Tipre
Nov 4, 2016·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Gang ChengAbass Alavi
Dec 15, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Katie Leach, Karen J Gregory
Mar 27, 2015·Molecular Pharmacology·Karen J Gregory, P Jeffrey Conn

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