A novel phosphodiesterase 10A (PDE10A) tracer candidate
Abstract
A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and for dose selection in clinical development.
We report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC–MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (KD) and PDE10A target density (Bmax) were determined to be 0.94 nM and 2.3 pmol/mg protein, respectively, using [3H]5 on rat striatum homogenate. Autoradiography on rat brain sections indicated that the tracer signal was consistent with known PDE10A expression pattern. The specific binding of [3H]5 to rat brain was blocked by another structurally distinct, published PDE10A inhibitor, MP-10. Lastly, our tracer was used to measure in vivo PDE10A target occupancy of a PDE10A inhibitor in rats using LC–MS/MS technology.
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This article has been cited by 3 ACS Journal articles (3 most recent appear below).
Discovery of Clinical Candidate 1-(4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)
Essa Hu, Ning Chen, Matthew P. Bourbeau, Paul E. Harrington, Kaustav Biswas, Roxanne K. Kunz, Kristin L. Andrews, Samer Chmait, Xiaoning Zhao, Carl Davis, Ji Ma, Jianxia Shi, Dianna Lester-Zeiner, Jean Danao, Jessica Able, Madelyn Cueva, Santosh Talreja, Thomas Kornecook, Hang Chen, Amy Porter, Randall Hungate, James Treanor, and Jennifer R. AllenJournal of Medicinal Chemistry2014 57 (15), 6632-6641Discovery of Clinical Candidate 1-(4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)
EssaHu, NingChen, Matthew P.Bourbeau, Paul E.Harrington, KaustavBiswas, Roxanne K.Kunz, Kristin L.Andrews, SamerChmait, XiaoningZhao, CarlDavis, JiMa, JianxiaShi, DiannaLester-Zeiner, JeanDanao, JessicaAble, MadelynCueva, SantoshTalreja, ThomasKornecook, HangChen, AmyPorter, RandallHungate, JamesTreanor, and Jennifer R.AllenJournal of Medicinal Chemistry2014 57 (15), 6632-6641We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-...
Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)
Essa Hu, Kristin Andrews, Samer Chmait, Xiaoning Zhao, Carl Davis, Silke Miller, Geraldine Hill Della Puppa, Mary Dovlatyan, Hang Chen, Dianna Lester-Zeiner, Jessica Able, Christopher Biorn, Ji Ma, Jianxia Shi, James Treanor, and Jennifer R. AllenACS Medicinal Chemistry Letters2014 5 (6), 700-705Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)
EssaHu, KristinAndrews, SamerChmait, XiaoningZhao, CarlDavis, SilkeMiller, GeraldineHill Della Puppa, MaryDovlatyan, HangChen, DiannaLester-Zeiner, JessicaAble, ChristopherBiorn, JiMa, JianxiaShi, JamesTreanor, and Jennifer R.AllenACS Medicinal Chemistry Letters2014 5 (6), 700-705We report the discovery of novel imidazo[4,5-b]pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole 1, which exhibited single digit nanomolar PDE10A activity but poor oral ...
Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)
Essa Hu, Roxanne K. Kunz, Ning Chen, Shannon Rumfelt, Aaron Siegmund, Kristin Andrews, Samer Chmait, Sharon Zhao, Carl Davis, Hang Chen, Dianna Lester-Zeiner, Ji Ma, Christopher Biorn, Jianxia Shi, Amy Porter, James Treanor, and Jennifer R. AllenJournal of Medicinal Chemistry2013 56 (21), 8781-8792
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