Preclinical Aspects of Nicotinic Acetylcholine Receptor Imaging

Recent developments in radiochemistry have opened new vistas for investigations of nicotinergic acetylcholine receptors (nAChRs) in living brain by positron emission tomography (PET) and by single photon emission computed tomography (SPECT). In parallel, dedicated instrumentation for molecular imaging in small animals has facilitated preclinical investigations in a number of models in which perturbations in nAChR signalling are implicated, notably Alzheimer’s disease and other neurodegenerative conditions, schizophrenia and other neuropsychiatric disorders, substance abuse and traumatic brain injury. The nAChRs are members of a family of ligand-gated ion channels composed of five subunits, most commonly occurring in the central nervous system as heteropentamers designated α4β2, with lesser amounts of the α7 homopentamer. We present a systematic review of preclinical findings with the diverse nAChR ligands which have been investigated to date. Molecular imaging of the α4β2 nAChR subtype by PET has been successfully achieved by 2-[18F]fluoro-A-85380. Newer agents such as (−)-[18F]flubatine permit quantitation of α4β2 receptors with PET recordings not exceeding 90 min, without the toxicity characteristic of earlier epibatidine derivatives. Imaging studies of α7 nAChRs have been hampered by inadequate pharmacological specificity of available ligands and by the low natural abundance of this receptor subtype in the brain. However, a continued search for optimal ligands is justified by the particular association of α7 nAChRs with aspects of cognitive function. We note that no molecular imaging ligands have been developed for α6-containing nAChRs, despite their importance for the psychopharmacology of nicotine actions in the basal ganglia. Finally, we review the competitive binding model, in which the availability of α4β2 binding sites is altered by competition from endogenous acetylcholine, noting that this approach has yet to be applied for monitoring acetylcholine release in disease models.