Pre-clinical validation of a novel alpha-7 nicotinic receptor radiotracer, [(3)H]AZ11637326: target localization, biodistribution and ligand occupancy in the rat brain
| Autor: | Charles S. Elmore, Geraldine Hill, David Gurley, John C. Gordon, Russell Bialecki, Emily Einstein, Jeffrey S. Smith, David Tuke, Min Ding, Jennifer L. Werkheiser, Mark S. Eisman, Donna L. Maier, Mary J. Bock |
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| Rok vydání: | 2010 |
| Předmět: |
Male
alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class Drug Evaluation Preclinical Biology Pharmacology Receptors Nicotinic Ligands Tritium Rats Sprague-Dawley Cellular and Molecular Neuroscience chemistry.chemical_compound Drug Delivery Systems Radioligand medicine Animals Spiro Compounds Tissue Distribution Methyllycaconitine Dose-Response Relationship Drug Brain Ligand (biochemistry) Receptor antagonist Rats Nicotinic agonist chemistry Alpha-7 nicotinic receptor Alpha-4 beta-2 nicotinic receptor AR-R17779 Azabicyclo Compounds Protein Binding |
| Zdroj: | Neuropharmacology. 61(1-2) |
| ISSN: | 1873-7064 |
| Popis: | The alpha-7 neuronal nicotinic receptor is a novel pharmacological target for psychiatric and cognitive disorders. Selective radiotracer tools for pre-clinical receptor occupancy can facilitate the interpretation of the biological actions of small molecules at a target receptor. We discovered a high affinity nicotinic alpha-7 subtype-selective ligand, AZ11637326, with physical–chemical and pharmacokinetic properties suitable for an in vivo radioligand tool. [3H]AZ11637326 synthesis by tritiodehalogenation of the corresponding tribromide precursor yielded a high specific activity radiotracer with high affinity alpha-7 receptor binding in the rat hippocampus determined by autoradiography (Kd = 0.2 nM). When [3H]AZ11637326 was administered to rats by intravenous bolus, rapid uptake was measured in the brain followed by a 3–4 fold greater specific binding in regions containing the alpha-7 receptor (frontal cortex, hippocampus, hypothalamus and midbrain) when compared to non-target regions (striatum and cerebellum). Systemic administration of the high affinity alpha-7 receptor antagonist, methyllycaconitine (MLA), or pretreatment with alpha-7 selective agonists (AR-R17779, PyrQTC, DBCO-4-POM, and DBCO-3-POM) significantly blocked the alpha-7 specific binding of [3H]AZ11637326 in the rat brain. The rank order of ligand ED50 values for in vivo alpha-7 receptor occupancy in rat hippocampus was: DBCO-4-POM > DBCO-3-POM ∼ MLA > PyrQTC > AR-R17779. The occupancy affinity shift was consistent with in vitro binding affinity in autoradiography. Our studies established the optimal conditions for [3H]AZ11637326 in vivo specific binding in the rat brain and support the use of [3H]AZ11637326 as a pre-clinical tool for assessment of novel alpha-7 compounds in drug discovery. |
| Databáze: | OpenAIRE |
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