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

• Published in: Acta pharmacologica Sinica 2021-03, Vol.42 (3), p.491
• Main Authors: Sun, Ji-Yun, Kumata, Katsushi, Chen, Zhen, Zhang, Yi-Ding, Chen, Jia-Hui, Hatori, Akiko, Fu, Hua-Long, Rong, Jian, Deng, Xiao-Yun, Yamasaki, Tomoteru, Xie, Lin, Hu, Kuan, Fujinaga, Masayuki, Yu, Qing-Zhen, Shao, Tuo, Collier, Thomas Lee, Josephson, Lee, Shao, Yi-Han, Du, Yun-Fei, Wang, Lu, Xu, Hao, Zhang, Ming-Rong, Liang, Steven H
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - metabolism; Acetamides - pharmacokinetics; Animals; Brain - metabolism; Carbon Radioisotopes - chemistry; Female; Ligands; Male; Methylation; Mice; Mice, Inbred ICR; Positron-Emission Tomography; Pyrimidines - chemical synthesis; Pyrimidines - metabolism; Pyrimidines - pharmacokinetics; Pyrroles - chemical synthesis; Pyrroles - metabolism; Pyrroles - pharmacokinetics; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - metabolism; Radiopharmaceuticals - pharmacokinetics; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 1745-7254

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 C-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 [ C]31 and [ C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [ C]CH I in good radiochemical yields (decay-corrected 28% and 32% relative to starting [ C]CO , respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/μmol). In particular, PET ligand [ C]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 [ C]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.