Development of novel radiopharmaceuticals for diagnostic imaging of sigma receptors in human brain and non-invasive visualization of sigma receptor positive tumors

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。本研究基于构效关系设计了新型放射性碘配体，并进行了合成和表征。在新合成的化合物中，125-I标记的2- bon和3- bon{1-（2和3- [125-I]碘苯丙基）-4-（3,4-二甲氧基苄基）哌嗪}对sigma受体具有非常高的亲和力和选择性。这两种放射性配体在小鼠和大鼠体内的生物分布研究显示，大脑对这两种配体的快速摄取和特异性脑积累与体内受体密度一致。特别是125-I标记的2-BON，利用放射自显影技术可以非常清晰地显示大鼠脑内的sigma受体。125-I标记的2-BON对肿瘤细胞上表达的sigma受体也显示出非常高的亲和力和特异性，并发现A-375肿瘤细胞中sigma受体的数量是大鼠大脑的10倍。这些结果表明，125-I标记的2-BON，以其I-123标记的形式，可以作为一种有前途的放射性药物来成像人脑中的sigma受体，并使用SPECT来观察体内非侵入性sigma受体阳性肿瘤。

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 ligands were designed based on structure-activity relationship, synthesized and characterized. Among the newly synthesized compounds, both 125-I labeled 2-BON and 3-BON {1-(2 and 3- [125-I]iodophenylpropyl)-4-(3,4-dimethoxybenzyl)piperazine} were found to possess very high affinity and selectivity for sigma receptors. Biodistribution studies of these two radioligands in mice and rats showed rapid brain uptake and specific brain accumulation consistent with sigma receptor density in vivo. Especially, 125-I labeled 2-BON visualized sigma receptors in rat brain very clearly using autoradiography.125-I labeled 2-BON also showed very high affinity and specificity for the sigma receptors expressed on tumor cells and revealed that A-375 tumor cells had 10 times more sigma receptors than the rat brain.These results suggest that 125-I labeled 2-BON, in its I-123 labeled form, could serve as a promising radiopharmaceutical to image sigma receptors in human brain and to visualize non-invasively sigma receptor positive tumors in vivo using SPECT.