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Synthesis and preliminary evaluation of novel 11C-labeled GluN2B-selective NMDA receptor negative allosteric modulators

   
@article{APS10292,
	author = {Ji-yun Sun and Katsushi Kumata and Zhen Chen and Yi-ding Zhang and Jia-hui Chen and Akiko Hatori and Hua-long Fu and Jian Rong and Xiao-yun Deng and Tomoteru Yamasaki and Lin Xie and Kuan Hu and Masayuki Fujinaga and Qing-zhen Yu and Tuo Shao and Thomas Lee Collier and Lee Josephson and Yi-han Shao and Yun-fei Du and Lu Wang and Hao Xu and Ming-rong Zhang and Steven H Liang},
	title = {Synthesis and preliminary evaluation of novel  11 C-labeled GluN2B-selective NMDA receptor negative allosteric modulators},
	journal = {Acta Pharmacologica Sinica},
	volume = {42},
	number = {3},
	year = {2021},
	keywords = {},
	abstract = {N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two 11C-labeled GluN2B-selective negative allosteric modulators (NAMs) containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging. Two PET ligands, namely [11C]31 and [11C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [11C]CH3I in good radiochemical yields (decay-corrected 28% and 32% relative to starting [11C]CO2, respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/μmol). In particular, PET ligand [11C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [11C]31 (up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10292}
}