The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging

被引：26

作者：

Zhang, Lei ^{[1
]}

Chen, Laigao ^{[2
]}

Beck, Elizabeth M. ^{[1
]}

Chappie, Thomas A. ^{[1
]}

Coelho, Richard V. ^{[3
]}

Doran, Shawn D. ^{[4
]}

Fan, Kuo-Hsien ^{[3
]}

Helal, Christopher J. ^{[5
]}

Humphrey, John M. ^{[5
]}

Hughes, Zoe ^{[6
]}

Kuszpit, Kyle ^{[3
]}

Lachapelle, Erik A. ^{[5
]}

Lazzaro, John T. ^{[4
]}

Lee, Chewah ^{[5
]}

Mather, Robert J. ^{[6
]}

Patel, Nandini C. ^{[1
]}

Skaddan, Marc B. ^{[3
]}

Sciabola, Simone ^{[1
]}

Verhoest, Patrick R. ^{[1
]}

Young, Joseph M. ^{[5
]}

Zasadny, Kenneth ^{[3
]}

Villalobos, Anabella ^{[7
]}

机构：

[1] Pfizer Inc, Med Design, Med Chem, Cambridge, MA 02139 USA

[2] Pfizer Inc, Clin & Translat Imaging, Early Clin Dev, Cambridge, MA 02139 USA

[3] Pfizer Inc, Bioimaging Ctr, Groton, CT 06340 USA

[4] Pfizer Inc, Med Design Pharmacokinet Dynam & Metab, Groton, CT 06340 USA

[5] Pfizer Inc, Med Design, Med Chem, Groton, CT 06340 USA

[6] Pfizer Inc, Internal Med Res Unit, Cambridge, MA 02139 USA

[7] Pfizer Inc, Med Synth Technol, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 20期

关键词：

IN-VIVO; RECEPTOR OCCUPANCY; HUMAN BRAIN; 2A;

D O I：

10.1021/acs.jmedchem.7b01050

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：8538 / 8551

页数：14

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