Unsulfated DTPA- and DOTA-CCK analogs as specific high-affinity ligands for CCK-B receptor-expressing human and rat tissues in vitro and in vivo
Unsulfated DTPA- and DOTA-CCK analogs as specific high-affinity ligands for CCK-B receptor-expressing human and rat tissues in vitro and in vivo
复制标题
DOI：
10.1007/s002590050247
复制
发表时间：
1998-05-01
期刊：
影响因子：
--
通讯作者：
Bugaj, JE
中科院分区：
文献类型：
--
作者：
Reubi, JC;Waser, B;Bugaj, JE
生长抑素或血管活性肠多肽等调节性多肽的受体在许多人类肿瘤中都有表达，并可以通过多肽受体闪烁技术在体内观察到。最近，CCK-B受体以高亲和力结合胃泌素和胆囊收缩素，在体外方法被证明在许多人类肿瘤组织中过表达，包括甲状腺髓样癌、小细胞肺癌、星形细胞瘤、胃肠道肿瘤和间质卵巢癌。在本研究中，我们设计了与金属螯合的DTPA和DOTA相连的新的、未硫化的CCK八肽类似物，并测试了它们与人肿瘤CCK-B受体阳性组织的结合亲和力：被检测到的最有效的化合物是DTPA-[NLE(28，31)]-CCK(26-33)(MP2286)和DTPA-[D-Asp(26)，NLE(28，31)]-CCK(26-33)(MP2288)，IC50为1.5 nM，用于比较，与C-末端的类似物，如[NLE(28，31)，APHE(33)(p-NH-DTPA)-CCK(26-33)和CCK-(26-33)-NH(CH2)(2)NH-DTPA的IC50为>；100海里。DOTA-[D-Asp(26)，NLE(28，31)]-CCK(26-33)的IC50为3.9 nM。这些化合物对CCK-B受体具有选择性，因为它们不与人类肿瘤(脑膜瘤或胃肠胰腺肿瘤)中表达的CCK-A受体高亲和力结合。铟-111标记的MP2286和MP2288在大鼠体内的生物分布研究表明，主要的清除方式是肾脏，主要摄取部位(%ID/g 24 h P.I.)肾脏(分别为0.270和0.262)和胃肠道。表达CCK-B受体的胃粘膜显示In-111标记的MP2288在体内特异性积聚，在存在过量的未标记MP2288时可以被阻断。In-111标记的MP2286和MP2288在人血浆中也是稳定的，而这两种化合物在尿液中都被降解(在37℃下3小时后降解40%)。这两个DTPA-CCK类似物的亲和力、特异性、生物分布和稳定性：表明这些化合物在体内可视化表达CCK-B受体的肿瘤方面有很大的应用前景。
Receptors for regulatory peptides such as somatostatin or vasoactive intestinal polypeptide are expressed by a number of human neoplasms and can be visualized in vivo with peptide receptor scintigraphy. Recently, the CCK-B receptor, which binds both gastrin and cholecystokinin with high affinity, was shown using in vitro methods to be overexpressed in a number of human tumor tissues, including medullary thyroid carcinomas, small cell lung cancers, astrocytomas, gastrointestinal tumors, and stromal ovarian cancers. In the present study, we have designed novel, unsulfated CCK octapeptide analogs linked to the metal chelating DTPA and DOTA, and have tested them for their binding affinity to CCK-B receptor-positive tissue from human tumors: The most potent compounds assayed were DTPA-[Nle(28,31)]-CCK(26-33) (MP2286) and DTPA-[D-Asp(26),Nle(28,31)]-CCK(26-33) (MP2288) with an IC50 of 1.5 nM, For comparison, analogs with C-terminal DTPA, such as [Nle(28,31),Aphe(33)(p-NH-DTPA)]-CCK(26-33) and CCK-(26-33)-NH(CH2)(2) NH-DTPA, had an IC50 of > 100 nM. DOTA-[D-Asp(26),Nle(28,31)]-CCK(26-33) had an IC50 Of 3.9 nM. The compounds were selective for CCK-B receptors as they did not bind with high affinity to CCK-A receptors expressed in human tumors (meningiomas or gastroenteropancreatic tumors). In vivo rat biodistribution studies with indium-111 labeled MP2286 and MP2288 showed that the primary mode of clearance was renal, and the primary sites of uptake (% ID/g 24 h p.i.) were kidneys (0.270 and 0.262, respectively) and the gastrointestinal tract. The CCK-B receptor-expressing gastric mucosa showed specific in vivo accumulation of In-111-labeled MP2288 which could be blocked in the presence of excess unlabeled MP2288. In-111-labeled MP2286 and MP2288 were also found to be stable in human plasma whereas both compounds were degraded in urine (>40% after 3 h at 37 degrees C). The affinity, specificity, biodistribution, and stability of these two DTPA-CCK analogs :indicate that these compounds have substantial promise for use in the in vivo visualization of CCK-B receptor-expressing tumors.