Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog.
Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog.
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DOI：
10.1007/s00259-010-1445-x
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发表时间：
2010-08
影响因子：
9.1
通讯作者：
Rivier, Jean E.
中科院分区：
文献类型：
--
作者：
Reubi, Jean Claude;Erchegyi, Judit;Cescato, Renzo;Waser, Beatrice;Rivier, Jean E.
肽受体靶向已成为一种越来越有吸引力的肿瘤诊断和放射治疗方法。为此目的，已开发出与多种螯合剂连接的肽。然而，它们很少被测试其激动或拮抗特性。我们在这里报道了一种生长抑素拮抗剂，它在与 DOTA 螯合剂偶联后转变为激动剂。使用受体放射自显影技术测试了两种新型生长抑素类似物 406-040-15 及其 DOTA 偶联对应物 406-051-20（带或不带冷铟标记）的 sst1-sst5 结合亲和力。此外，使用基于免疫荧光显微镜的内化测定，对它们在稳定表达人 sst2 或 sst3 受体的 HEK293 细胞中体外影响 sst2 和 sst3 内化的能力进行了功能测试。所有三种化合物均被表征为对所有五种生长抑素受体亚型具有高亲和力的泛生长抑素类似物。在sst2内化测定中，所有三种化合物均表现出相同的行为，即弱的激动作用辅以弱的拮抗作用，与部分激动剂的行为相一致。相反，在 sst3 内化测定中，406-040-15 是完全拮抗剂，而其 DOTA 对应物 406-051-20（带或不带铟标记）则转变为完全激动剂。将 DOTA 螯合剂添加到生长抑素类似物 406-040-15 中会触发 sst3 受体从拮抗剂转变为激动剂。这表明用于肿瘤靶向的潜在放射性配体在进一步开发之前应始终进行功能测试，特别是在添加螯合剂的情况下。
Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium-labeling, were tested for their sst1-sst5 binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst2 and sst3 internalization in vitro in HEK293 cells stably expressing the human sst2 or sst3 receptor, using an immunofluorescence microscopy based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five somatostatin receptor subtypes. In the sst2 internalization assay, all three compounds showed an identical behavior, namely a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA counterpart, 406-051-20, with and without Indium-labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should be always tested functionally before further development, in particular if a chelator is added.
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DOI：
10.1007/s00259-002-0761-1
发表时间：
2002-05-01
影响因子：
9.1
作者：
Gotthardt, M;Fischer, M;Behr, TM
通讯作者：
Behr, TM
DOI：
10.1007/s00259-002-1040-x
发表时间：
2003-02-01
影响因子：
9.1
作者：
Nock, B;Nikolopoulou, A;Maina, T
通讯作者：
Maina, T
影响因子：
11.5
作者：
Mansi, Rosalba;Wang, Xuejuan;Maecke, Helmut R.
通讯作者：
Maecke, Helmut R.
影响因子：
3.6
作者：
Liu, QS;Cescato, R;Schonbrunn, A
通讯作者：
Schonbrunn, A
DOI：
10.1124/jpet.104.067306
发表时间：
2004-09-01
影响因子：
3.5
作者：
Schlag, BD;Lou, ZW;Dunlop, J
通讯作者：
Dunlop, J