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

西格玛受体一直是研究的焦点，因为它们有可能为精神病、运动障碍和神经变性的机制提供新的见解。最近，高密度的西格玛受体已在几种肿瘤来源的细胞系中得到证实。针对西格玛受体的SPECT和PET放射性药物将作为运动障碍和某些精神疾病的诊断工具，以及对体内表达西格玛受体的肿瘤的无创可视化具有重要价值。本研究根据构效关系设计了新型放射性碘配体[^<125>I]o-BON {1-（2-[^<125>I]碘苯丙基）-4-（3,4-二甲氧基苯乙基）哌嗪}，并进行了合成和表征。[^<125>I]o-BON对sigma受体具有非常高的亲和力和选择性。采用大鼠大脑中动脉（MCA）闭塞模型和体外放射自显影技术研究了[^<125>I]o-BON在脑内的分布，并与脑血流（CBF）进行了比较。在梗死区域，[^<125>I]o-BON的积累随着CBF的减少而减少。然而，在缺血但重要的区域，特别是海马ca1区，观察到相对于CBF， [^<125>I]o-BON的积累增加。这些数据表明[^<125>I]o-BON可能提供基于不同于CBF的sigma受体的功能信息，并且[^<125>I]o-BON是一种潜在的有用的脑缺血成像和病理生理评估的放射性示踪剂。

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.