Characterization of [(3)H]CHIBA-1001 binding to alpha7 nicotinic acetylcholine receptors in the brain from rat, monkey, and human.
Accumulating evidence suggests that the alpha7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer's disease. Currently, there are no suitable small molecule radioligands for alpha7 nAChRs in the brain, although [(125)I]alpha-bungarotoxin has been widely used as a radioligand for alpha7 nAChRs. In the present study, we characterized a new radioligand, 4-[(3)H]methylphenyl 2,5-diazabicyclo[3.2.2]nonane-2-carboxylate ([(3)H]CHIBA-1001), a derivative of the selective alpha7 nAChR agonist SSR180711, in brain membranes from rat, monkey, and human. Scatchard analysis revealed an apparent equilibrium dissociation constant (Kd) of 193.4nM in rat brain membranes at 4 degrees C, and the maximal number of binding sites (Bmax) was 346.2fmol/mg protein. The order of drugs for the inhibition of [(3)H]CHIBA-1001 binding to rat brain membranes is SSR180711>A-844606>MG624>epibatidine>DMAB>A-582941, suggesting a similarity of alpha7 nAChR pharmacological profiles. In contrast, alpha-bungarotoxin, MLA, and nicotine were found to be very weak. The distribution of [(3)H]CHIBA-1001 binding to crude membranes from dissected regions of rat, monkey, and human brain was different from that of [(125)I]alpha-bungarotoxin binding, suggesting that [(3)H]CHIBA-1001 binding sites may not be identical to [(125)I]alpha-bungarotoxin binding in the brain. In summary, [(3)H]CHIBA-1001 would be a useful radioligand for alpha7 nAChRs in the brains of rodents, non-human primates, and humans.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
Yuko
Y
Tanibuchi
Jin
J
Wu
Jun
J
Toyohara
Yuko
Y
Fujita
Masaomi
M
Iyo
Kenji
K
Hashimoto
D000368:Aged; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002038:Bungarotoxins / Q000378:metabolism / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D018678:Cholinergic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007456:Iodine Isotopes / Q000378:metabolism / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014018:Tissue Distribution / Q000502:physiology; D014316:Tritium / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; C533046:CHIBA 1001; D018678:Cholinergic Agents; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D007456:Iodine Isotopes; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014316:Tritium