Development of ligands for in vivo imaging of cerebral nicotinic receptors

Nicotinic acetylcholine receptors (nAChRs) mediate a variety of brain funct ions. Findings from postmortem studies and clinical investigations have imp licated them in the pathophysiology and treatment of Alzheimer's and Parkin son's diseases and other CNS disorders (e.g. Tourette's syndrome, epilepsy, nicotine dependence). Therefore, it ultimately might be useful to image nA ChRs noninvasively for diagnosis, for studies on how changes in nAChRs migh t contribute to cerebral disorders, for development of therapies targeted a t nAChRs, and to monitor the effects of such treatments. To date, only (S)- (-)-nicotine, radiolabeled with C-11, has been used for external imaging of nAChRs in human subjects. Since this radiotracer presents drawbacks, new l igands, with more favorable properties, have been synthesized and tested. T hree general classes of compounds, namely, nicotine and its analogs, epihat idine and related compounds, and 3-pyridyl ether compounds, including A-853 80, have been evaluated. Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the alph a 4 beta 2 subtype of nAChRs. (C) 2000 Elsevier Science B.V. All rights res erved.