Metal-ion-dependent biological properties of a chelator-derived somatostatin analogue for tumour targeting
Metal-ion-dependent biological properties of a chelator-derived somatostatin analogue for tumour targeting
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DOI：
10.1002/chem.200701264
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发表时间：
2008-01-01
影响因子：
4.3
通讯作者：
Maecke, Helmut R.
中科院分区：
文献类型：
--
作者：
Heppeler, Axel;Andre, Joao P.;Maecke, Helmut R.
基于生长抑素的放射性配体已被证明对神经内分泌肿瘤及其转移具有灵敏的成像特性。评价了[Co-55（dotatoc）]（dotatoc = 4，7，10-三羧甲基-1，4，7，10-四氮杂环十二烷-1-基乙酰基-D-Phe-（Cys-Tyr-D-Trp-Lys-Thr-Cys）-苏氨醇（二硫键））作为PET用新型放射性药物的潜力。以Co-57作为正电子发射体Co-55的替代物，采用两种裸鼠模型研究了[Co-57（dotatoc）]的药代动力学。用放射自显影法测定了[Co-nat（dotatoc）]在转染人生长抑素受体亚型的膜上生长抑素受体亚型（sst 1-sst 5）的亲和力。这些研究表明，[Co-57（dotatoc）]是一种sst 2特异性放射肽，对sst 2受体亚型具有迄今为止发现的最高亲和力。AR 4 - 2 J细胞系的内化率也是任何生长抑素基放射性肽中发现的最高的。在携带AR 4 - 2 J肿瘤或转染的HEK-sst 2细胞肿瘤的裸鼠中进行的生物分布研究显示，肿瘤和其他sst受体表达组织中的高特异性摄取，这反映了高受体结合亲和力和高内化率。本文根据螯合模型[Co-II（dota）]（2-）和[Ga-III（dota）]（-）的结构参数讨论了[Co-57（dotatoc）]和[Ga-67（dotatoc）]之间的药理学差异。这两种螯合物显示六倍协调的pseudocatahedral安排。
Somatostatin-based radioligands have been shown to have sensitive imaging properties for neuroendocrine tumours and their metastases. The potential of [Co-55(dotatoc)] (dotatoc = 4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-ylacetyl-D-Phe-(Cys-Tyr-D-Trp-Lys-Thr-Cys)-threoninol (disulfide bond)) as a new radiopharmaceutical agent for PET has been evaluated. Co-57 was used as a surrogate of the positron emitter Co-55 and the pharmacokinetics of [Co-57(dotatoc)] were investigated by using two nude mouse models. The somatostatin receptor subtype (sst1-sst5) affinity profile of [Co-nat(dotatoc)] on membranes transfected with human somatostatin receptor subtypes was assessed by using autoradiographic methods. These studies revealed that [Co-57(dotatoc)] is an sst2-specific radiopeptide which presents the highest affinity ever found for the sst2 receptor subtype. The rate of internalisation into the AR4-2J cell line also was the highest found for any somatostatin-based radiopeptide. Biodistribution studies, performed in nude mice bearing an AR4-2J tumour or a transfected HEK-sst2 cell-based tumour, showed high and specific uptake in the tumour and in other sst-receptor-expressing tissues, which reflects the high receptor binding affinity and the high rate of internalisation. The pharmacologic differences between [Co-57(dotatoc)] and [Ga-67(dotatoc)] are discussed in terms of the structural parameters found for the chelate models [Co-II(dota)](2-) and [Ga-III(dota)](-) whose X-ray structures have been determined. Both chelates show six-fold coordination in pseudooctahedral arrangements.