Abstract
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. 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.). 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 rath...Continue Reading
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