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Development of novel radiopharmaceuticals for functional imaging of sigma receptors in human brain diseases.

开发用于人脑疾病中西格玛受体功能成像的新型放射性药物。

基本信息

批准号：
13670972
负责人：
OHMOMO Yoshiro
金额：
$ 1.98万
依托单位：
Osaka University of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670972/
关键词：
Sigma Receptor Brain Disease Radiopharmaceutical Nuclear Medicine Diagnostic Imaging SPECT

项目摘要

Sigma receptors have been the focus of intense study because of their potential to offer new insights into the mechanism of psychoses, movement disorders, and neurodegeneration. Recently, high densities of sigma receptors have been demonstrated in several tumor-derived cell lines. SPECT and PET radiopharmaceuticals specific for sigma receptors would be of great value as diagnostic tools for movement disorders and certain psychotic illness, and for non-invasive visualization of sigma receptor expressed tumors in vivo.In the present research, novel radioiodinated ligand [^<125>I]o-BON {1-(2-[^<125>I]iodophenyl-propyl)-4-(3,4-dimethoxyphenylethyl)piperazine} was designed based on structure-activity relationship, synthesized and characterized. [^<125>I]o-BON was found to possess very high affinity and selectivity for sigma receptors.Furthermore, we investigated brain distribution of [^<125>I]o-BON and compared it with cerebral blood flow (CBF) by using rat model of middle cerebral artery (MCA) occlusion and in vitro autoradiography technique. In the region of an infarct, accumulation of [^<125>I]o-BON decreased concurrently with CBF reduction. However, an increased accumulation of [^<125>I]o-BON relative to CBF was observed in ischemic but vital regions, especially in hippocampus CA1region. These data indicate that [^<125>I]o-BON may provide functional information based on sigma receptors different from CBF, and [^<125>I]o-BON is a potentially useful radiotracer for imaging and evaluating the pathophysiology of cerebral ischemia.

西格玛受体一直是深入研究的焦点，因为它们有可能为精神病、运动障碍和神经退行性疾病的机制提供新的见解。最近，在几种肿瘤来源的细胞系中已经证明了高密度的σ受体。特异性针对 σ 受体的 SPECT 和 PET 放射性药物作为运动障碍和某些精神疾病的诊断工具以及对体内 σ 受体表达肿瘤的无创可视化具有重要价值。在本研究中，新型放射性碘配体 [^125I]o-BON 根据构效关系设计、合成并表征了{1-(2-[^ 125 I]碘苯基-丙基)-4-(3，4-二甲氧基苯基乙基)哌嗪}。 [^<125>I]o-BON被发现对σ受体具有非常高的亲和力和选择性。此外，我们利用大脑中动脉(MCA)闭塞大鼠模型和体外放射自显影技术研究了[^<125>I]o-BON的脑分布，并与脑血流(CBF)进行比较。在梗塞区域，[^ 125 I]o-BON的积累与CBF减少同时减少。然而，在缺血但有活力的区域，特别是在海马CA1区域，观察到[^ 125 I]o-BON的积累相对于CBF增加。这些数据表明[^ 125 I]o-BON可以提供基于与CBF不同的σ受体的功能信息，并且[^ 125 I]o-BON是用于成像和评估脑缺血的病理生理学的潜在有用的放射性示踪剂。