Radiosynthesis of a 125I Analog of a Highly Selective Alpha3beta4 Nicotinic Acetylcholine Receptor Antagonist Ligand for Use in Autoradiography Studies

Abstract

The α3β4 subtype of the nicotinic acetylcholine receptors (nAChR) is present in limited but specific areas of the brain unlike the widely distributed α4β2 nAChR subtype, known to be involved in the addictive effects of nicotine. Recently, the α3β4 nAChR subtype has been linked to addiction to nicotine as well as other drugs of abuse. However, there have been no subtype-selective α3β4 nAChR ligands available to study the role of this receptor in drug addiction. Our laboratory has discovered a series of very high affinity and highly selective ligands for the α3β4 nAChR subtype. We now report the synthesis of a radiolabeled ¹²⁵I analog of N-(2-iodophenyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (AT-1012), a subnanomolar affinity, highly selective α3β4 nAChR ligand from this series. This analog, [¹²⁵I] AT-1012, was synthesized by a facile radio-iodination of a tributylstannylated precursor, which gave the radiolabeled compound with high specific activity and radiochemical purity. This high-affinity radioactive α3β4 nAChR antagonist is very useful as a pharmacological tool in autoradiography studies, to elucidate the localization of the α3β4 nAChR in the brain and study its pharmacology in the brain reward circuit.

Copyright © 2012 John Wiley & Sons, Ltd.