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The development of radiolabeled molecular imaging agents for diagnosing Alzheimer's disease.

用于诊断阿尔茨海默病的放射性标记分子成像剂的开发。

基本信息

批准号：
14570845
负责人：
SHIBA Kazuhiro
金额：
$ 2.18万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570845/
关键词：
sigma receptor iodovesamicol molecular imaging agent Alzheimer'z disease

项目摘要

We evaluated the potential of the (+)-enantiomer of radioiodinated 2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-[^<125>I]-p-iodovesamicol) [(+)-[^<125>I]pIV], radioiodinated at the para position of the 4-phenylpiperidine moiety, as a single photon emission computed tomography (SPECT) ligand for mapping sigma-1 receptor in the central nervous system.In competitive inhibition studies, (+)-pIV (Ki=1.3nM) had more than 10 times higher affinity to the sigma-1 (σ-1) receptor than (+)-pentazocine (Ki=19.9nM) or haloperidol (Ki=13.5nM) known as sigma ligands. Also, the binding affinity of (+)-pIV to the σ-1 receptor (Ki=1.3nM), was about 16 times higher than the sigma-2 (σ-2) receptor (Ki=20.4nM). (+)-pIV (Ki=1262nM) had a much lower affinity to VAChT than (-)-vesamicol (Ki=13.0nM) or (-)-pIV. (+)-[^<125>I]pIV had low affinity to the dopamine, serotonin, adrenaline and acetylcholine receptors. Furthermore, in a saturation binding study, (+)-[^<125>I]pIV exhibited a Kd of 6.96 nM with a maximum number of binding sites Bmax of 799.3 fmol/mg of protein.In vivo studies, significant amounts (approximately 3% of the injected dose) of (+)-[^<125>I]pIV accumulated in rat brain and its retention was prolonged. The accumulation of (+)-[^<125>I]pIV in the rat brain was significantly reduced by the co-administration of sigma ligands such as pentazocine or haloperidol. Ex vivo autoradiography of the rat brain at 1 hr following i.v. injection of (+)-[^<125>I]pIV showed high localization in brain areas rich in sigma-1 receptor. Thus, the distribution of (+)-[^<125>I]pIV was thought to bind to sigma-1 receptor in vivo. These results suggest that radioiodinated (+)-pIV may have the potential to image sigma-1 (σ-1) receptor in vivo, at least in animals.

我们评估了放射性碘标记的2-[4-（4-碘苯基）哌啶子基]环己醇（（+）-[13 <125>I]-p-碘维索霉素）[（+）-[13 <125>I]pIV]的（+）-对映体（在4-苯基哌啶部分的对位放射性碘标记）作为单光子发射计算机断层扫描（SPECT）配体用于定位中枢神经系统中的σ-1受体的潜力。（+）-pIV（Ki=1.3nM）对σ-1（σ-1）受体的亲和力比（+）-喷他佐辛高10倍以上（Ki=19.9nM）或氟哌啶醇（Ki=13.5nM），称为σ配体。此外，（+）-pIV与σ-1受体的结合亲和力（Ki=1.3nM）比σ-2（σ-2）受体的结合亲和力（Ki=20.4nM）高约16倍。（+）-pIV（Ki= 1262 nM）与VAChT的亲和力远低于（-）-vesamicol（Ki=13.0nM）或（-）-pIV。（+）-[^<125>I]pIV对多巴胺、5-羟色胺、肾上腺素和乙酰胆碱受体具有低亲和力。此外，在饱和结合研究中，（+）-[^<125>I]pIV显示Kd为6.96 nM，最大结合位点数Bmax为799.3 fmol/mg蛋白质。在体内研究中，大量（约为注射剂量的3%）的（+）-[^<125>I]pIV在大鼠脑中蓄积，并且其保留时间延长。通过<125>共同给予σ配体如喷他佐辛或氟哌啶醇，（+）-[^ I]pIV在大鼠脑中的蓄积显著降低。静脉注射（+）-[^ I]pIV后1小时，大鼠脑的离体放射自显影<125>显示在富含sigma-1受体的脑区中高度定位。因此，认为（+）-[^<125>I]pIV的分布在体内与σ-1受体结合。这些结果表明，放射性碘标记的（+）-pIV可能具有在体内（至少在动物中）成像sigma-1（σ-1）受体的潜力。