PF-05212377 succinate

PF-05212377, also known as SAM-760 and WYE-103760, is a selective serotonin 5-HT6 receptor antagonist developed by Wyeth and later Pfizer. The EBC product is a 1:1 salt of the active compound and succinic acid, with the molecular formula C22H26N4O6S. The PF-05212377 succinate molecular weight is approximately 474.53 g/mol; 474.157 is its monoisotopic mass. CAS 3096657-56-3 identifies the salt and distinguishes it from the free base, CAS 1226793-34-5, with a molecular weight of 356.44 g/mol.

Application of PF-05212377 succinate

PF-05212377 succinate is used to investigate 5-HT6 pharmacology in neuroscience and cognition research. It supports receptor-binding, target-occupancy, and translational studies connecting biochemical potency with central nervous system exposure. Published PET and clinical results make it a useful reference for assessing whether receptor binding and brain occupancy translate into functional effects.

In Vitro

In a radioligand-binding assay using 3 nM [3H]-LSD, PF-05212377 bound the human 5-HT6 receptor with a Ki of 0.53 nM and an IC50 of 1.06 nM. These values describe the active PF-05212377 component, not the succinate counterion. In human in vitro systems, the compound was identified as a P-glycoprotein substrate but not a BCRP substrate, which is relevant when relating potency to unbound brain exposure.

In Vivo

Rodent studies reported modulation of glutamatergic and cholinergic signaling in the cortex and hippocampus, with pro-cognitive effects in behavioral models. PET studies demonstrated dose- and concentration-dependent 5-HT6 occupancy in non-human primates and healthy volunteers. In humans, occupancy approached 80% at doses of 15 mg or more, with an estimated unbound plasma EC50 of 0.37 nM.

Pfizer PF-05212377 succinate was evaluated as SAM-760 in a Phase 2 trial in patients with mild-to-moderate Alzheimer's disease receiving stable donepezil. They received 30 mg once daily or placebo for 12 weeks. Although up to 342 participants were planned, 186 were randomized before the study stopped for futility. No significant cognitive or neuropsychiatric benefit was found, and the compound remains investigational.

Biochemical and Physiological Actions

The 5-HT6 receptor is a Gs-coupled serotonin receptor expressed predominantly in the central nervous system. PF-05212377 prevents its activation and alters downstream neuronal signaling. The PF-05212377 succinate molecular structure contains the receptor-active benzimidazole component and succinic acid as the counterion. Changes in acetylcholine and glutamate release are downstream network effects; the circuitry linking 5-HT6 blockade to cognition is not fully established.

Features and Benefits of PF-05212377 succinate

• Sub-nanomolar affinity for the human 5-HT6 receptor in a defined binding assay.
• PET-confirmed target engagement in non-human primates and humans.
• A defined 1:1 PF-05212377 succinate chemical structure on the EBC product page.
• Published negative Phase 2 results that provide a useful translational benchmark.

Before experimental use, confirm the PF-05212377 succinate structure, purity, assay, and salt composition against the product-specific certificate of analysis.