Reubi J C, Waser B, Schaer J C, Laederach U, Erion J, Srinivasan A, Schmidt M A, Bugaj J E
Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Switzerland.
Eur J Nucl Med. 1998 May;25(5):481-90. doi: 10.1007/s002590050247.
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-[Nle28, 31]-CCK(26-33) (MP2286) and DTPA-[d-Asp26,Nle28,31]-CCK(26-33) (MP2288) with an IC50 of 1.5 nM. For comparison, analogs with C-terminal DTPA, such as [Nle28,31,Aphe33(p-NH-DTPA)]-CCK(26-33) and CCK-(26-33)-NH(CH2)2 NH-DTPA, had an IC50 of >100 nM. DOTA-[D-Asp26, Nle28,31]-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 111In-labeled MP2288 which could be blocked in the presence of excess unlabeled MP2288. 111In-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.
生长抑素或血管活性肠多肽等调节肽的受体在多种人类肿瘤中表达，并且可以通过肽受体闪烁显像在体内进行可视化。最近，使用体外方法显示，对胃泌素和胆囊收缩素均具有高亲和力的CCK - B受体在多种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、胃肠道肿瘤和卵巢基质癌。在本研究中，我们设计了与金属螯合剂二乙三胺五乙酸（DTPA）和四氮杂环十二烷四乙酸（DOTA）相连的新型、无硫酸化的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：所检测的最有效化合物是DTPA - [Nle28, 31] - CCK(26 - 33)（MP2286）和DTPA - [d - Asp26,Nle28,31] - CCK(26 - 33)（MP2288），其半数抑制浓度（IC50）为1.5 nM。作为比较，具有C末端DTPA的类似物，如[Nle28,31,Aphe33(p - NH - DTPA)] - CCK(26 - 33)和CCK - (26 - 33) - NH(CH2)2 NH - DTPA，IC50大于100 nM。DOTA - [D - Asp26, Nle28,31] - CCK(26 - 33)的IC50为3.9 nM。这些化合物对CCK - B受体具有选择性，因为它们对人类肿瘤（脑膜瘤或胃肠胰腺肿瘤）中表达的CCK - A受体没有高亲和力。用铟 - 111标记的MP2286和MP2288进行的体内大鼠生物分布研究表明，清除的主要途径是通过肾脏，摄取的主要部位（注射后24小时每克组织的百分注射剂量，% ID/g）是肾脏（分别为0.270和0.262）和胃肠道。表达CCK - B受体的胃黏膜显示出111In标记的MP2288在体内的特异性积聚，在存在过量未标记的MP2288时这种积聚可被阻断。111In标记的MP2286和MP2288在人血浆中也被发现是稳定的，而这两种化合物在尿液中均会降解（在37℃下3小时后降解>40%）。这两种DTPA - CCK类似物的亲和力、特异性、生物分布和稳定性表明，这些化合物在用于表达CCK - B受体肿瘤的体内可视化方面具有很大的前景。
