Synthesis and evaluation of [125I]I-TSA as a brain nicotinic acetylcholine receptor α7 subtype imaging agent

IntroductionSome in vitro investigations have suggested that the nicotinic acetylcholine receptor (nAChR) α7 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 α7 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 α7 nAChR in brain.MethodsIn 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 [125I]I-TSA. In vivo receptor blocking studies were carried out by treating mice with methyllycaconitine (MLA; 5 nmol/5 μl, i.c.v.) or nonradioactive I-TSA (50 μmol/kg, i.v.).ResultsI-TSA exhibited a high affinity and selectivity for the α7 nAChR (Ki for α7 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 (α7 nAChR-rich region) and was rather rapid in the cerebellum (α7 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.ConclusionDespite its high affinity and selectivity, [125I]I-TSA does not appear to be a suitable tracer for in vivo α7 nAChR receptor imaging studies due to its high nonspecific binding. Further structural optimization is needed.