期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 20, 页码 8538-8551出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01050
关键词
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As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (B (max)) and bio distribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS cold tracer method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the cold tracer study. In subsequent non-human primate (NHP) PET imaging studies, [F-18]8 showed rapid brain uptake and high target specificity, indicating that [F-18]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.
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