Preclinical and clinical aspects of nicotinic acetylcholine receptor imaging

Innovations in radiochemistry and pharmacology are opening new vistas for studies of nicotinergic acetylcholine receptors (nAChRs) in human brain by positron emission tomography (PET) and by single-photon emission computed tomography (SPECT). In parallel, instrumentation optimized for molecular imaging in rodents facilitates preclinical studies in models of human diseases with perturbed nAChR signalling, notably Alzheimer’s disease and other neurodegenerative conditions, schizophrenia and other neuropsychiatric disorders, substance abuse, and traumatic brain injury. The nAChRs are ligand-gated ion channels composed of five subunits forming a central pore for cation flux. The most abundant nAChRs in the central nervous system are heteropentamers (designated α4β2), followed by the α7 homopentamer. We present a systematic review of published findings with the various nAChR ligands using imaging techniques in vivo, emphasizing preclinical models and human studies.. Molecular PET imaging of the α4β2 nAChR subtype with the antagonist 2-[18F]fluoro-A-85380 is hampered by the long acquisition times. Newer agents such as (-)-[18F]flubatine, [18F]XTRA or [18F]nifene permit quantitation of α4β2 receptors with PET recordings lasting 90 minutes or less, and without the toxicity risk of earlier epibatidine derivatives. The early PET studies of α7 nAChRs suffered from low pharmacological specificity, further hampered by low natural abundance of the receptor. However, several good α7 nAChR ligands such as [18F]ASEM and [18F]DBT10 have emerged in the past few years. There are still no ligands selective for α6-containing nAChRs, despite their importance for nicotine-induced dopamine release in striatum. Selective α3β4 nAChR radioligands are under development, but remain untested in clinical studies of depression and addiction. Several nAChR ligands find use for pharmacological occupancy studies, and competition from endogenous acetylcholine reduces α4β2 binding site availability, a property that enables monitoring by PET of acetylcholine release in living brain.