The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging
| Autor: | Nandini Chaturbhai Patel, Richard V. Coelho, Christopher John Helal, Chewah Lee, Anabella Villalobos, Shawn D. Doran, Joseph Michael Young, Robert J. Mather, Simone Sciabola, Erik Alphie Lachapelle, John T. Lazzaro, Thomas Allen Chappie, Patrick Robert Verhoest, Zoë A. Hughes, Marc B. Skaddan, Elizabeth Mary Beck, John M. Humphrey, Kyle Kuszpit, Laigao Chen, Lei Zhang, Kenneth R. Zasadny, Kuo-Hsien Fan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Biodistribution Phosphodiesterase Inhibitors Pharmacology Radioligand Assay Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Tandem Mass Spectrometry In vivo Drug Discovery medicine Radioligand Animals Structure–activity relationship Cerebral Cortex medicine.diagnostic_test Chemistry Phosphodiesterase Ligand (biochemistry) Cyclic Nucleotide Phosphodiesterases Type 4 Macaca fascicularis 030104 developmental biology Positron emission tomography Positron-Emission Tomography Molecular Medicine 030217 neurology & neurosurgery Chromatography Liquid |
| Zdroj: | Journal of Medicinal Chemistry. 60:8538-8551 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 (Bmax) and biodistribution 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, [18F]8 showed rapid brain uptake and high target specificity, indicating that [18F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging. |
| Databáze: | OpenAIRE |
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