The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging.
Lei ZhangLaigao ChenElizabeth M BeckThomas A ChappieRichard V CoelhoShawn D DoranKuo-Hsien FanChristopher J HelalJohn M HumphreyZoe HughesKyle KuszpitErik A LachapelleJohn T LazzaroChewah LeeRobert J MatherNandini C PatelMarc B SkaddanSimone SciabolaPatrick R VerhoestJoseph M YoungKenneth ZasadnyAnabella VillalobosPublished in: Journal of medicinal chemistry (2017)
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.
Keyphrases
- pet imaging
- positron emission tomography
- computed tomography
- pet ct
- endothelial cells
- small molecule
- resting state
- structure activity relationship
- poor prognosis
- high throughput
- binding protein
- blood brain barrier
- functional connectivity
- subarachnoid hemorrhage
- induced pluripotent stem cells
- cerebral ischemia
- single cell