Journal Article Synthesis and preliminary studies of a novel negative allosteric modulator [11C]QCA for imaging of metabotropic glutamate receptor 2

Zhang, Xiaofei  ,  Kumata, Katsushi  ,  Yamasaki, Tomoteru  ,  Cheng, Ran  ,  Hatori, Akiko  ,  Ma, Longle  ,  Zhang, Yiding  ,  Xie, Lin  ,  Wang, Lu  ,  Jin Kang, Hye  ,  J. Sheffler, Douglas  ,  D. P. Cosford, Nicholas  ,  Ming-Rong, Zhang  ,  H.Liang, Steven

8 ( 9 )  , pp.1937 - 1948 , 2017-05
Metabotropic glutamate 2 receptors (mGlu2) are involved in the pathogenesis of severalCNS disorders and neurodegenerative diseases. Pharmacological modulation of this target represents apotential disease-modifying approach for the treatment of substance abuse, depression, schizophreniaand dementias. While quantification of mGlu2 receptors in the living brain by positron emissiontomography (PET) would help us better understand signaling pathways relevant to these conditions,few successful examples have been demonstrated to image mGlu2 in vivo and a suitable PET tracer isyet to be identified. Herein we report the design and synthesis of a radiolabeled negative allostericmodulator (NAM) for mGlu2 PET tracerdevelopment based on a quinoline 2-carboxamidescaffold. The most promising candidate,7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide([11C]QCA) was prepared in 13% radiochemicalyield (non-decay corrected at the end of synthesis) with >99% radiochemical purity and >74GBq/μmol (2 Ci/μmol) specific activity. While the tracer showed limited brain uptake (0.3 SUV),probably attributable to effects on PgP/Bcrp eff lux pump, in vitro autoradiography studiesdemonstrated heterogeneous brain distribution and specific binding. Thus, [11C]QCA is achemical probe that

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