title: Synthesis and evaluation of [125I]I-TSA as a brain nicotinic acetylcholine receptor alpha7 subtype imaging agent.
abstract: BACKGROUND
  Some in vitro investigations have suggested that the nicotinic acetylcholine receptor (nAChR) alpha7 subtype is implicated in Alzheimer's disease, schizophrenia and others. Recently, we developed (R)-3'-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'-[1',3']oxazolidin]-2'-one (Br-TSA), which has a high affinity and selectivity for alpha7 nAChRs. Therefore we synthesized (R)-3'-(5-[125I]iodothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'-[1',3']oxazolidin]-2'-one ([125I]I-TSA) and evaluated its potential for the in vivo detection of alpha7 nAChR in brain.
  
  
  METHODS
  In vitro binding affinity of I-TSA was measured in rat brain homogenates. Radioiodination was accomplished by a Br-I exchange reaction. Biodistribution studies were undertaken in mice by tail vein injection of [(125)I]I-TSA. In vivo receptor blocking studies were carried out by treating mice with methyllycaconitine (MLA; 5 nmol/5 mul, i.c.v.) or nonradioactive I-TSA (50 micromol/kg, i.v.).
  
  
  RESULTS
  I-TSA exhibited a high affinity and selectivity for the alpha7 nAChR (K(i) for alpha7 nAChR = 0.54 nM). Initial uptake in the brain was high (4.42 %dose/g at 5 min), and the clearance of radioactivity was relatively slow in the hippocampus (alpha7 nAChR-rich region) and was rather rapid in the cerebellum (alpha7 nAChR poor region). The hippocampus to cerebellum uptake ratio was 0.9 at 5 min postinjection, but it was increased to 1.8 at 60 min postinjection. Although the effect was not statistically significant, administration of I-TSA and MLA decreased the accumulation of radioactivity in hippocampus.
  
  
  CONCLUSIONS
  Despite its high affinity and selectivity, [125I]I-TSA does not appear to be a suitable tracer for in vivo alpha7 nAChR receptor imaging studies due to its high nonspecific binding. Further structural optimization is needed.
authors.affiliation: Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu 431-3192, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Ogawa
authors.forename: Ryo
authors.initials: R
authors.lastname: Tatsumi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fujio
authors.forename: Jiro
authors.initials: J
authors.lastname: Katayama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Magata
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D008297:Male; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis*; D049268:Positron-Emission Tomography; D011812:Quinuclidines / Q000138:chemical synthesis*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C515563:3'-(5-iodothiophen-2-yl)spiro(1-azabicyclo(2.2.2)octane-3,5'-(1',3')oxazolidin)-2'-one; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D010080:Oxazoles; D011812:Quinuclidines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor