In vitro and in vivo evaluation of 64Cu-Labeled DOTA-Linker-Bombesin(7-14) analogues containing different amino acid linker moieties
In vitro and in vivo evaluation of 64Cu-Labeled DOTA-Linker-Bombesin(7-14) analogues containing different amino acid linker moieties
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DOI：
10.1021/bc0603788
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发表时间：
2007-07-01
影响因子：
4.7
通讯作者：
Rogers, Buck E.
中科院分区：
文献类型：
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作者：
Parry, Jesse J.;Kelly, Thomas S.;Rogers, Buck E.
胃泌素释放肽受体（GRPR）在多种肿瘤类型上过表达，并已被放射性标记肽靶向用于检测和治疗这些癌症。14个氨基酸的蛙皮素（BN）肽的类似物已经用γ-和正电子发射的放射性核素进行放射性标记，用于检测表达GRPR的肿瘤。我们先前已经评估了用正电子发射体铜-64（Cu-64）放射性标记的BN类似物，其含有置于BN肽和1，4，7，10-四氮杂环十二烷-1，4，7，10-四乙酸（DOTA）螯合剂之间的各种脂肪族连接体。这些研究表明，类似物可用于小鼠GRPR阳性肿瘤的正电子发射断层扫描（PET）成像，但临床转化将受到背景组织中显著摄取的阻碍。因此，本研究的目的是确定在DOTA螯合物和BN肽之间放置氨基酸接头的使用是否会减少非靶组织摄取，同时保持良好的前列腺肿瘤摄取。所研究的接头利用甘氨酸（G）、丝氨酸（S）或谷氨酸（E）的三种氨基酸组合。在PC-3细胞中的体外测定显示，含谷氨酸的接头具有差的结合和内化，而其他类似物具有<100 nM的IC 50值和良好的内化。在体内，这些相同的类似物表现出肿瘤特异性摄取和良好的成像特性，与先前报道的Cu-64标记的DOTA-BN类似物相当或更好。总的来说，这项研究表明，BN类似物含有氨基酸接头可用于表达GRPR的前列腺癌的PET成像，这些接头导致较低的背景组织摄取。
The gastrin-releasing peptide receptor (GRPR) is overexpressed on a variety of tumor types and has been targeted with radiolabeled peptides for detection and therapy of these cancers. Analogues of the 14 amino acid bombesin (BN) peptide have been radiolabeled with both gamma- and positron-emitting radionuclides for detection of GRPR-expressing tumors. We have previously evaluated BN analogues radiolabeled with the positron-emitter, copper-64 (Cu-64), that contained various aliphatic linkers placed between the BN peptide and the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. These studies showed that the analogues could be used for positron-emission tomographic (PET) imaging of GRPR-positive tumors in mice but clinical translation would be hindered by significant uptake in background tissues. Therefore, the purpose of this study was to determine if the use of amino acid linkers placed between the DOTA chelate and the BN peptide would reduce nontarget tissue uptake, while maintaining good prostate tumor uptake. The linkers studied utilized three amino acid combinations of glycine (G), serine (S), or glutamic acid (E). In vitro assays in PC-3 cells showed that the glutamic acid-containing linkers had poor binding and internalization, while the other analogues had IC50 values < 100 nM and good internalization. In vivo, these same analogues demonstrated tumor-specific uptake and good imaging characteristics that were comparable to, or better than the previously reported Cu-64-labeled DOTA-BN analogues. Overall, this study shows that BN analogues containing amino acid linkers can be used for the PET imaging of GRPR-expressing prostate cancer and that these linkers lead to lower background tissue uptake.