Synthesis and evaluation of [125I]I-TSA as a brain nicotinic acetylcholine receptor alpha7 subtype imaging agent.
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.
Ogawa
Mikako
M
Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu 431-3192, Japan.
Tatsumi
Ryo
R
Fujio
Masakazu
M
Katayama
Jiro
J
Magata
Yasuhiro
Y
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
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