PF-06445974

PF-06445974, a promising positron emission tomography (PET) lead, has exquisite potency at PDE4B with an IC50 <1 nM. The IC50 values are 36, 4.7 and 17 nM for PDE4D, PDE4A and PDE4C, respectively. PF-06445974 has good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study[1].

Signaling Pathways >> Metabolic Enzyme/Protease >> Phosphodiesterase (PDE)

Research Areas >> Neurological Disease

PDE4B:<1 nM (IC50)

PDE4D:36 nM (IC50)

PDE4A:4.7 nM (IC50)

PDE4C:17 nM (IC50)

PF-06445974 demonstrates minimal off-target activities in broad-spectrum selectivity panels, with only weak µM activities at PDE10 (IC50=2290 nM), PDE5A (IC50=4640 nM) and GABAA (Ki=3850 nM)[1].

PF-06445974 exhibits high central nervous system (CNS) PET MPO score (4.0). PF-06445974 is a promising radiotracer lead for specific binding assessment. Neuropharmacokinetic study in rats (0.1 mg/kg, IV) confirms high brain permeability with a total brain to plasma ratio of 0.76, corresponding to a free brain to plasma ratio of 0.70[1]. Animal Model: Twenty-five drug-naive male 129/B6 PDE4D KO mice (25-35 g)[1] Dosage: 10 µg/kg Administration: Dosed intravenously at 10 µg/kg in a 5 mL/kg dosing volume Result: Showed excellent brain uptake and reached peak concentrations at around 20 minutes.

[1]. Lei Zhang, et al. The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging. J Med Chem. 2017 Oct 26;60(20):8538-8551.