title: 5-Iodo-A-85380 binds to alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as alpha4beta2* subtypes.
abstract: Recent work suggests that 5-iodo-A-85380, a radioiodinated analog of the 3-pyridyl ether A-85380, represents a promising imaging agent for non-invasive, in vivo studies of alphaAbeta2* nicotinic acetylcholine receptors (nAChRs; *denotes receptors containing the indicated subunits), because of its low non-specific binding, low in vivo toxicity and high selectivity for alpha4beta2* nAChRs. As an approach to elucidate nAChR subtypes expressed in striatum, we carried out competitive autoradiography in monkey and rat brain using 5-[125I]iodo-A-85380 ([125I]A-85380) and [125I]alpha-conotoxin MII, a ligand that binds with high affinity to alpha6* and alpha3* nAChRs, but not to alpha4beta2* nAChRs. Although A-85380 is reported to be selective for alpha4beta2* nAChRs, we observed that A-85380 completely inhibited [125I]alpha-conotoxin MII binding in rat striatum and that A-85380 blocked >90% of [125I] alpha-conotoxin MII sites in monkey caudate and putamen. These results suggest that A-85380 binds to non-alpha4beta2* nAChRs, including putative alpha6* nAChRs. Experiments to determine the percentage of [125I]A-85380 sites that contain alpha-conotoxin MII-sensitive (alpha6beta2*) nAChRs indicate that they represent about 10% of [125I]A-85380 sites in rodent striatum and about 30% of sites in monkey caudate and putamen. These data are important for identifying alterations in nicotinic receptor subtypes in Parkinson's disease and other basal ganglia disorders both in in vitro and in in vivo imaging studies.
authors.affiliation: The Parkinson's Institute, Sunnyvale, California 94089-1605, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kulak
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Sum
authors.forename: John L
authors.initials: JL
authors.lastname: Musachio
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D000818:Animals; D001345:Autoradiography; D001384:Azetidines / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects*; D002421:Caudate Nucleus / Q000378:metabolism; D020916:Conotoxins / Q000493:pharmacokinetics*; D003342:Corpus Striatum / Q000378:metabolism; D007457:Iodine Radioisotopes; D008024:Ligands; D018733:Nicotinic Antagonists / Q000493:pharmacokinetics*; D011699:Putamen / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D012453:Saimiri
chemical_list: C104288:A 85380; D001384:Azetidines; D020916:Conotoxins; D007457:Iodine Radioisotopes; D008024:Ligands; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; C403531:nicotinic receptor alpha4beta2