与DOTA、NOTA和NODAGA共轭并用(64)Cu、(68)Ga和(111)In标记的放射性标记小分子胃泌素类似物的正电子发射断层扫描(PET)和单光子发射计算机断层扫描(SPECT)成像
PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with (64)Cu, (68)Ga, and (111)In.
作者信息
Roosenburg S, Laverman P, Joosten L, Cooper M S, Kolenc-Peitl P K, Foster J M, Hudson C, Leyton J, Burnet J, Oyen W J G, Blower P J, Mather S J, Boerman O C, Sosabowski J K
机构信息
Department of Radiology and Nuclear Medicine, Radboud University Medical Center , 6500 HB Nijmegen, The Netherlands.
出版信息
Mol Pharm. 2014 Nov 3;11(11):3930-7. doi: 10.1021/mp500283k. Epub 2014 Jul 11.
Cholecystokinin-2 (CCK-2) receptors, overexpressed in cancer types such as small cell lung cancers (SCLC) and medullary thyroid carcinomas (MTC), may serve as targets for peptide receptor radionuclide imaging. A variety of CCK and gastrin analogues has been developed, but a major drawback is metabolic instability or high kidney uptake. The minigastrin analogue PP-F11 has previously been shown to be a promising peptide for imaging of CCK-2 receptor positive tumors and was therefore further evaluated. The peptide was conjugated with one of the macrocyclic chelators DOTA, NOTA, or NODAGA. The peptide conjugates were then radiolabeled with either (68)Ga, (64)Cu, or (111)In. All (radio)labeled compounds were evaluated in vitro (IC50) and in vivo (biodistribution and PET/CT and SPECT/CT imaging). IC50 values were in the low nanomolar range for all compounds (0.79-1.51 nM). In the biodistribution studies, (68)Ga- and (111)In-labeled peptides showed higher tumor-to-background ratios than the (64)Cu-labeled compounds. All tested radiolabeled compounds clearly visualized the CCK2 receptor positive tumor in PET or SPECT imaging. The chelator did not seem to affect in vivo behavior of the peptide for (111)In- and (68)Ga-labeled peptides. In contrast, the biodistribution of the (64)Cu-labeled peptides showed high uptake in the liver and in other organs, most likely caused by high blood levels, probably due to dissociation of (64)Cu from the chelator and subsequent transchelation to proteins. Based on the present study, (68)Ga-DOTA-PP-F11 might be a promising radiopharmaceutical for PET/CT imaging of CCK2 receptor expressing tumors such as MTC and SCLC. Clinical studies are warranted to investigate the potential of this tracer.
胆囊收缩素-2(CCK-2)受体在小细胞肺癌(SCLC)和甲状腺髓样癌(MTC)等癌症类型中过表达,可作为肽受体放射性核素显像的靶点。已开发出多种CCK和胃泌素类似物,但一个主要缺点是代谢不稳定或肾脏摄取率高。小胃泌素类似物PP-F11先前已被证明是用于CCK-2受体阳性肿瘤显像的一种有前景的肽,因此对其进行了进一步评估。该肽与大环螯合剂DOTA、NOTA或NODAGA之一进行偶联。然后用(68)Ga、(64)Cu或(111)In对肽偶联物进行放射性标记。对所有(放射性)标记化合物进行了体外(IC50)和体内(生物分布以及PET/CT和SPECT/CT显像)评估。所有化合物的IC50值均处于低纳摩尔范围(0.79 - 1.51 nM)。在生物分布研究中,(68)Ga和(111)In标记的肽显示出比(64)Cu标记的化合物更高的肿瘤与本底比值。所有测试的放射性标记化合物在PET或SPECT显像中均能清晰显示CCK2受体阳性肿瘤。对于(111)In和(68)Ga标记的肽,螯合剂似乎不影响肽的体内行为。相比之下,(64)Cu标记肽的生物分布显示在肝脏和其他器官中有高摄取,这很可能是由于血液水平高导致的,可能是因为(64)Cu从螯合剂上解离并随后转螯合到蛋白质上。基于本研究,(68)Ga-DOTA-PP-F11可能是用于MTC和SCLC等表达CCK2受体肿瘤的PET/CT显像的一种有前景的放射性药物。有必要开展临床研究以探究这种示踪剂的潜力。