Novel 64Cu- and 68Ga-Labeled RGD Conjugates Show Improved PET Imaging of αvβ3 Integrin Expression and Facile Radiosynthesis
Novel 64Cu- and 68Ga-Labeled RGD Conjugates Show Improved PET Imaging of αvβ3 Integrin Expression and Facile Radiosynthesis
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新型 64Cu 和 68Ga 标记的 RGD 结合物可改善αvβ3 整合素表达的 PET 成像，且易于放射合成
DOI：
10.2967/jnumed.111.087700
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发表时间：
2011-08-01
影响因子：
9.3
通讯作者：
Fani, Melpomeni
中科院分区：
文献类型：
--
作者：
Dumont, Rebecca A.;Deininger, Friederike;Fani, Melpomeni
F-18标记的精氨酸-甘氨酸-天冬氨酸(RGD)多肽PET可以可视化和定量检测患者的α(V)β(3)整合素的表达，但放射性标记复杂，某些肿瘤类型的图像对比度有限。鉴于Ga-68的生产和放射性标记的便利性，开发Ga-68-RGD多肽将是非常有用的，而铜--RGD多肽允许延迟成像，潜在地改善了肿瘤与背景的比率。方法：分别用三氮杂环己烷、1，4，7-三氮杂环酮、1-戊二酸-4，7-乙酸和十六烷4，11-bis(carboxymethyl)-1，4，8，11-tetraazabicyclo[6.6.2](CB-TE2a)对环五肽c(RGDfK)用Ga-68或Cu-进行放射性标记。NODAGA-c(RGDfK)在室温下用两种放射性核素在10min内标记。对其他结合物使用95℃孵育长达30分钟。通过基于细胞的受体结合分析评价了金属多肽的亲和力。在裸鼠皮下移植U87 MG胶质母细胞瘤模型上进行了小动物PET研究和生物分布研究。结果：标记物的放化纯度大于97%，比活度为15~20GBq/mMol。所有金属多肽的亲和力分布相似，并与参考标准c(RGDfV)相当。在生物分布研究中，所有化合物在注射后1小时显示出相对相似的肿瘤和正常的器官摄取，这与已发表的F-18标记的RGD多肽的数据相似。然而，在注射后18h，铜--诺达加-c(RGDfK)和铜--CB-TE2a-c(RGDfK)显示肿瘤与器官的比率增加了20倍。PET研究显示了U87 MG肿瘤在18h的高对比度图像，证实了生物分布数据。结论：Ga-68-NODAGA-c(RGDfK)易于放射性标记，是F-18标记的RGD多肽的一种有吸引力的替代品。铜--NODAGA-c(RGDfK)和铜--CB-TE2a-c(RGDfK)在18小时内的高肿瘤背景比(RGDfK)为检测铜-标记的RGD多肽提供了依据。
PET with F-18-labeled arginine-glycine-aspartic acid (RGD) peptides can visualize and quantify alpha(v)beta(3) integrin expression in patients, but radiolabeling is complex and image contrast is limited in some tumor types. The development of Ga-68-RGD peptides would be of great utility given the convenience of Ga-68 production and radiolabeling, and Cu-64-RGD peptides allow for delayed imaging with potentially improved tumor-to-background ratios. Methods: We used the chelators DOTA, 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid (NODAGA), and 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] hexadecane (CB-TE2A) to radiolabel the cyclic pentapeptide c(RGDfK) with Ga-68 or Cu-64. NODAGA-c(RGDfK) was labeled at room temperature with both radionuclides within 10 min. Incubation at 95 degrees C for up to 30 min was used for the other conjugates. The affinity profile of the metallopeptides was evaluated by a cell-based receptor-binding assay. Small-animal PET studies and biodistribution studies were performed in nude mice bearing subcutaneous U87MG glioblastoma xenografts. Results: The conjugates were labeled with a radiochemical purity greater than 97% and specific activities of 15-20 GBq/mu mol. The affinity profile was similar for all metallopeptides and comparable to the reference standard c(RGDfV). In the biodistribution studies, all compounds demonstrated a relatively similar tumor and normal organ uptake at 1 h after injection that was comparable to published data on F-18-labeled RGD peptides. At 18 h after injection, however, Cu-64-NODAGA-c(RGDfK) and Cu-64-CB-TE2A-c(RGDfK) showed up to a 20-fold increase in tumor-to-organ ratios. PET studies demonstrated high-contrast images of the U87MG tumors at 18 h, confirming the biodistribution data. Conclusion: The ease of radiolabeling makes Ga-68-NODAGA-c(RGDfK) an attractive alternative to F-18-labeled RGD peptides. The high tumor-to-background ratios of Cu-64-NODAGA-c(RGDfK) and Cu-64-CB-TE2A-c(RGDfK) at 18 h warrant testing of Cu-64-labeled RGD peptides in patients.