Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[(11)C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2.
Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[(11)C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2.
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DOI：
10.1021/acschemneuro.7b00098
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发表时间：
2017-09-20
影响因子：
5
通讯作者：
Liang SH
中科院分区：
文献类型：
--
作者：
Zhang X;Kumata K;Yamasaki T;Cheng R;Hatori A;Ma L;Zhang Y;Xie L;Wang L;Kang HJ;Sheffler DJ;Cosford NDP;Zhang MR;Liang SH
代谢型谷氨酸2受体(MGlu2)参与了多种中枢神经系统疾病和神经退行性疾病的发病机制。这一靶点的药理调节代表了治疗药物滥用、抑郁症、精神分裂症和痴呆症的一种潜在的疾病修正方法。虽然通过正电子发射断层扫描(PET)对活体大脑中mGlu2受体的定量将有助于我们更好地了解与这些情况相关的信号通路，但很少有成功的例子被证明在体内对mGlu2进行成像，并且还没有确定合适的PET示踪剂。在这里，我们报道了一种基于喹啉2-甲酰胺支架的放射性标记负变构调节剂(NAM)的设计和合成，用于mGlu2 PET示踪剂的开发。最有希望的候选7-((2，5-dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl)喹啉-2-甲酰胺([11C]QCA)的合成以13%的放化产率(合成结束时校正的未衰变)和>；99%的放化纯度和>；74GBq/微克分子(2Ci/微克分子)的比活度被制备出来。虽然示踪剂显示脑部摄取有限(0.3SUV)，可能是由于对PGP/BCRP外流泵的影响，但体外放射自显影研究显示脑部分布不均和特异性结合。因此，[11C]QCA是一种化学探针，为开发新一代mGlu2 PET示踪剂奠定了基础。
Metabotropic glutamate 2 receptors (mGlu2) are involved in the pathogenesis of several CNS disorders and neurodegenerative diseases. Pharmacological modulation of this target represents a potential disease-modifying approach for the treatment of substance abuse, depression, schizophrenia and dementias. While quantification of mGlu2 receptors in the living brain by positron emission tomography (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 is yet to be identified. Herein we report the design and synthesis of a radiolabeled negative allosteric modulator (NAM) for mGlu2 PET tracer development based on a quinoline 2-carboxamide scaffold. 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% radiochemical yield (non-decay corrected at the end of synthesis) with >99% radiochemical purity and >74 GBq/µmol (2 Ci/µmol) specific activity. While the tracer showed limited brain uptake (0.3 SUV), probably attributable to effects on PgP/Bcrp efflux pump, in vitro autoradiography studies demonstrated heterogeneous brain distribution and specific binding. Thus, [11C]QCA is a chemical probe that provides the basis for the development of a new generation mGlu2 PET tracers.
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影响因子：
4.6
作者：
Harpsøe K;Isberg V;Tehan BG;Weiss D;Arsova A;Marshall FH;Bräuner-Osborne H;Gloriam DE
通讯作者：
Gloriam DE
影响因子：
4
作者：
Chiechio, Santina;Nicoletti, Ferdinando
通讯作者：
Nicoletti, Ferdinando
影响因子：
7.3
作者：
Felts, Andrew S.;Rodriguez, Alice L.;Emmitte, Kyle A.
通讯作者：
Emmitte, Kyle A.
影响因子：
3.2
作者：
Golubeva, Anna V.;Moloney, Rachel D.;Cryan, John F.
通讯作者：
Cryan, John F.
DOI：
10.1124/jpet.106.117093
发表时间：
2007-07-01
影响因子：
3.5
作者：
Hemstapat, Kamondanai;Da Costa, Herve;Conn, P. Jeffrey
通讯作者：
Conn, P. Jeffrey