Preclinical Melanoma Imaging with 68Ga-Labeled α-Melanocyte-Stimulating Hormone Derivatives Using PET
Preclinical Melanoma Imaging with 68Ga-Labeled α-Melanocyte-Stimulating Hormone Derivatives Using PET
复制标题
使用 PET 使用 68Ga 标记的 α-黑素细胞刺激激素衍生物进行临床前黑色素瘤成像
作者：
Chengcheng Zhang;Zhengxing Zhang;Kuo‐Shyan Lin;Jinhe Pan;Iulia Dude;Navjit Hundal;N. Colpo;F. Bénard
据估计，2016年美国有76，380例新病例和10，130例死亡。黑皮质素1受体（MC 1 R）在绝大多数黑色素瘤中高度表达，这使其成为分子成像和放射性核素治疗的有吸引力的靶点。已成功开发并研究了内酰胺桥环化α-促黑素细胞激素（Ac-Nle 4-cyclo[Asp 5-His-D-Phe 7-Arg-Trp-Lys 10]-NH 2，或Nle-CycMSHhex）类似物，用于MC 1 R靶向成像，主要是单光子发射计算机断层扫描（SPECT）。本研究的目的是设计和评价新的肽用于黑色素瘤成像与正电子发射断层扫描（PET）。我们设计并合成了三个肽，DOTA-PEG 2-Nle-CycMSHhex（CCZ 01047）、DOTA-4-氨基-（1-羧甲基）哌啶（Pip）-Nle-CycMSHhex（CCZ 01048）和DOTA-Pip-Pip-Nle-CycMSHhex（CCZ 01056）。所有三种肽均表现出对MC 1 R的高结合亲和力（具有亚纳摩尔Ki值）、快速内化到B16 F10黑素瘤细胞中以及高体内稳定性（在注射后15分钟（p.i.）在血浆中。所有三种68 Ga标记的示踪剂在携带B16 F10肿瘤的C57 BL/6 J小鼠中产生高对比度PET图像，并且它们各自的肿瘤摄取在注射后1小时分别为8.0 ± 3.0、12.3 ± 3.3和6.5 ± 1.4%ID/g。在感染后1小时观察到最小的正常器官活动，除了肾脏（分别为5.1 ± 1.4、4.7 ± 0.5和6.2 ± 2.0% ID/g）和甲状腺（CCZ 01047为4.1 ± 0.6% ID/g，CCZ 01048为2.4 ± 0.6% ID/g）。由于68 Ga-CCZ 01048在肿瘤部位的高积累和快速背景清除，我们在感染后2小时进一步评估了它，观察到肿瘤摄取为21.9 ± 4.6%ID/g，背景活性进一步降低。还实现了异常的图像对比度，即肿瘤与血液、肿瘤与肌肉、肿瘤与骨和肿瘤与肾的比值分别为96.4 ± 13.9、210.9 ± 20.9、39.6 ± 11.9和4.0 ± 0.9。还通过共注射过量的非放射性Ga偶联的CCZ 01048进行阻断研究，其证实肿瘤摄取是MC 1 R介导的。总之，将阳离子Pip接头引入Nle-CycMSHhex，CCZ 01048，不仅改善了肿瘤摄取，而且在临床前黑色素瘤模型中产生了与PET成像的高肿瘤与正常组织对比度。因此，CCZ 01048是一种有希望的黑色素瘤PET成像候选物，并且当用α或β发射体标记时，可能作为黑色素瘤放射性核素治疗的治疗诊断剂。
It is estimated that melanoma accounted for 76,380 new cases and 10,130 deaths in the United States in 2016. The melanocortin 1 receptor (MC1R) is highly expressed in the vast majority of melanomas, which makes it an attractive target for molecular imaging and radionuclide therapy. Lactam bridge-cyclized α-melanocyte-stimulating hormone (Ac-Nle4-cyclo[Asp5-His-D-Phe7-Arg-Trp-Lys10]-NH2, or Nle-CycMSHhex) analogues have been successfully developed and studied for MC1R-targeted imaging, predominantly with single-photon emission computed tomography (SPECT). The goal of this study was to design and evaluate novel peptides for melanoma imaging with positron emission tomography (PET). We designed and synthesized three peptides, DOTA-PEG2-Nle-CycMSHhex (CCZ01047), DOTA-4-amino-(1-carboxymethyl) piperidine (Pip)-Nle-CycMSHhex (CCZ01048), and DOTA-Pip-Pip-Nle-CycMSHhex (CCZ01056). All three peptides exhibited high binding affinity to MC1R with sub-nanomolar Ki values, rapid internalization into B16F10 melanoma cells and high in vivo stability with more than 93% remaining intact at 15 min post-injection (p.i.) in blood plasma. All three 68Ga-labeled tracers produced high contrast PET images in C57BL/6J mice bearing B16F10 tumors, and their respective tumor uptakes were 8.0 ± 3.0, 12.3 ± 3.3, and 6.5 ± 1.4 %ID/g at 1 h p.i. Minimal normal organ activity was observed at 1 h p.i., except for kidneys (5.1 ± 1.4, 4.7 ± 0.5, and 6.2 ± 2.0 %ID/g, respectively), and thyroid (4.1 ± 0.6 %ID/g for CCZ01047 and 2.4 ± 0.6 %ID/g for CCZ01048). Due to high accumulation at tumor sites and rapid background clearance of 68Ga-CCZ01048, we further evaluated it at 2 h p.i., and a tumor uptake of 21.9 ± 4.6 %ID/g was observed, with background activity further decreased. Exceptional image contrast was also achieved, i.e. tumor-to-blood, tumor-to-muscle, tumor-to-bone and tumor-to-kidney ratios were 96.4 ± 13.9, 210.9 ± 20.9, 39.6 ± 11.9 and 4.0 ± 0.9, respectively. A blocking study was also performed by co-injection of excess amount of non-radioactive Ga-coupled of CCZ01048, which confirmed that the tumor uptake was MC1R mediated. In conclusion, the introduction of a cationic Pip linker to Nle-CycMSHhex, CCZ01048, not only improved tumor uptake, but also generated high tumor-to-normal tissue contrast with PET imaging in a preclinical melanoma model. Therefore, CCZ01048 is a promising candidate for PET imaging of melanoma, and potentially as a theranostic agent for radionuclide therapy of melanoma when labeled with α or β emitters.
影响因子：
4.7
作者：
Cheng, Zhen;Xiong, Zhengming;Gambhir, Sanjiv Sam
通讯作者：
Gambhir, Sanjiv Sam
影响因子：
4.9
作者：
Guo H;Gallazzi F;Miao Y
通讯作者：
Miao Y