Ogawa Mikako, Tatsumi Ryo, Fujio Masakazu, Katayama Jiro, Magata Yasuhiro
Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu 431-3192, Japan.
Nucl Med Biol. 2006 Apr;33(3):311-6. doi: 10.1016/j.nucmedbio.2005.12.016. Epub 2006 Mar 9.
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 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.
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.
一些体外研究表明，烟碱型乙酰胆碱受体（nAChR）α7亚型与阿尔茨海默病、精神分裂症等疾病有关。最近，我们开发了（R）-3'-（5-溴噻吩-2-基）螺[1-氮杂双环[2.2.2]辛烷-3,5'-[1',3']恶唑烷]-2'-酮（Br-TSA），它对α7 nAChRs具有高亲和力和选择性。因此，我们合成了（R）-3'-（5-[¹²⁵I]碘噻吩-2-基）螺[1-氮杂双环[2.2.2]辛烷-3,5'-[1',3']恶唑烷]-2'-酮（[¹²⁵I]I-TSA），并评估了其在体内检测脑内α7 nAChR的潜力。
在大鼠脑匀浆中测量I-TSA的体外结合亲和力。通过Br-I交换反应完成放射性碘化。通过尾静脉注射[（¹²⁵）I]I-TSA在小鼠中进行生物分布研究。通过用甲基lycaconitine（MLA；5 nmol/5 μl，脑室内注射）或非放射性I-TSA（50 μmol/kg，静脉注射）处理小鼠进行体内受体阻断研究。
I-TSA对α7 nAChR表现出高亲和力和选择性（α7 nAChR的K（i）= 0.54 nM）。脑内的初始摄取量很高（5分钟时为4.42 %剂量/克），放射性清除在海马体（富含α7 nAChR的区域）相对较慢，而在小脑（α7 nAChR缺乏区域）则相当快。注射后5分钟时海马体与小脑的摄取比为0.9，但在注射后60分钟时增加到1.8。尽管效果无统计学意义，但给予I-TSA和MLA可降低海马体中放射性的积累。
尽管[¹²⁵I]I-TSA具有高亲和力和选择性，但由于其高非特异性结合，它似乎不是体内α7 nAChR受体成像研究的合适示踪剂。需要进一步的结构优化。
