A-186253, a specific antagonist of the α4β2 nAChRs: its properties and potential to study brain nicotinic acetylcholine receptors

• Published in: Neuropharmacology Vol. 47; no. 4; pp. 538 - 557
• Main Authors: Itier, Valérie, Schönbächler, Roland, Tribollet, Eliane, Honer, Michael, Prinz, Katja, Marguerat, Anouk, Bertrand, Sonia, Bunnelle, William H., Schubiger, P.August, Meyer, Michael D., Sullivan, James P., Bertrand, Daniel, Westera, Gerrit
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-09-2004
• Subjects: Autoradiography; Brain; Electrophysiology; Imaging; Neuronal nicotinic receptors; Radiolabeling; Radiolabeling; Electrophysiology; Brain; Autoradiography; Neuronal nicotinic receptors; Imaging
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2004.05.006

Imaging the living brain and the distribution of the ligand gated channels that participate in the neurotransmission is one of the challenges that is hoped to bring new insights for the treatment of neurological diseases. Herein, we probed a new nicotinic derivative, A-186253 as a potential molecule to discriminate with high resolution the different neuronal nicotinic receptor subtypes that are expressed in distinct brain areas. Binding with a high affinity of 440 pM at the major brain α4β2 receptor subtype and presenting an excellent safety margin, properties of the A-186253 were thoroughly evaluated. While autoradiography confirmed its specificity for the α4β2 subtype, functional investigations revealed for short exposures a broader spectrum of action at receptors including the ganglionic α3β4 and the homomeric α7 subtypes. Specificity was, however, observed at α4β2 when receptors were exposed for several minutes with low concentration of the A-186253. In view of these promising results, the A-186253 was radiolabeled and tested in positron emission tomography on rats and pigs. Despite the high selectivity observed in vitro, the A-186253 displayed a complex binding profile and little displacement by the agonist cytisine. While the A-186253 can be valuable to discriminate receptor subtypes, improvements of this molecule must be brought for in vivo measurements.