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

Sigma受体一直是密集研究的焦点，因为它们有可能为精神病、运动障碍和神经退行性变的机制提供新的见解。近年来，在多种肿瘤细胞系中发现了高密度的Sigma受体。针对Sigma受体的SPECT和PET放射性药物对于运动障碍和某些精神疾病的诊断以及活体肿瘤中Sigma受体表达的非侵入性可视化具有重要的价值。在新合成的化合物中，125I标记的2-Bon和3-Bon{1-(2和3-[125-I]iodophenylpropyl)-4-(3，4-dimethoxybenzyl)piperazine})都对Sigma受体具有很高的亲和力和选择性。这两种放射性配基在小鼠和大鼠体内的生物分布研究表明，它们在脑中的快速摄取和特定的脑积聚与体内的Sigma受体密度一致。尤其是~(125)I标记的2-Bon在放射自显影中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受体也显示出很高的亲和力和特异性，并且发现A-375肿瘤细胞中含有比大鼠脑中多10倍的sigma受体。这些结果表明，以I-123标记的125-I标记的2-Bon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，并利用SPECT在体内显示非侵袭性的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.