[18F]ZW-104, a New Radioligand for Imaging α2-α3-α4/β2 Central Nicotinic Acetylcholine Receptors: Evaluation in Mutant Mice

Positron emission tomography (PET) imaging of nicotinic acetylcholine receptors (nAChRs) containing α4 and β2 subunits is an important tool to study the role of nAChRs in various human brain disorders. Among well-studied radioligands, only 5-iodo-A-85380 underwent a detailed screening including the affinity for several nAChRs subtypes (Mukhin et al., 2000; Xiao and Kellar, 2004). Effects of a null β2 mutation in mice were also described (Mukhin et al., 2000). The presence of iodine at the 5-position or another bulky substituent of the pyridinyl ring in this compound increased the selectivity for α4β2 subtype when compared to A-85380 (Xiao and Kellar, 2004). Within a series of A-85380 derivatives bearing a 5-alkynyl substituent, we have been interested in the properties of the agonist 5-(6-fluorohexyn-1-yl)-3-[2(S)-2-azetidinylmethoxy] pyridine (ZW-104; Kozikowski et al., 2005), which is suitable for radiolabeling with fluorine-18 and was used for PET studies (Valette et al., 2009). To further characterize the binding profile of this compound, we carried out autoradiographic binding in wild-type and several a or b nAChR null-mutant mice. These autoradiographic studies provide important information on the regional distribution of the nAChRs labeled by the ligand, and so are complementary to membrane binding studies. (authors)