PET of Somatostatin Receptor-Positive Tumors Using 64Cu- and 68Ga-Somatostatin Antagonists: The Chelate Makes the Difference
PET of Somatostatin Receptor-Positive Tumors Using 64Cu- and 68Ga-Somatostatin Antagonists: The Chelate Makes the Difference
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使用 64Cu- 和 68Ga-Somatostatin 拮抗剂对生长抑素受体阳性肿瘤进行 PET 研究： 螯合物的作用
DOI：
10.2967/jnumed.111.087999
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发表时间：
2011-07-01
影响因子：
9.3
通讯作者：
Maecke, Helmut R.
中科院分区：
文献类型：
--
作者：
Fani, Melpomeni;Del Pozzo, Luigi;Maecke, Helmut R.
基于生长抑素的放射性标记肽已被成功地引入临床，用于生长抑素受体（sst）阳性肿瘤，特别是亚型2（sst 2）肿瘤的靶向显像和放射性核素治疗。临床上使用的肽仅为激动剂。最近，我们发现放射性标记的拮抗剂可能优于激动剂，因为它们显示出更好的药代动力学，包括更高的肿瘤摄取。决定放射性拮抗剂性能的因素很少被研究。在这里，我们报告的发展和评估的四个铜-64或镓-68放射性拮抗剂PET的SST 2阳性肿瘤。研究方法：新的拮抗剂p-Cl-Phecyclo（D-Cys-Tyr-D-4-amino-Phe（ammonoyl）-Lys-Thr-Cys）D-Tyr-NH 2（LM 3）与3种大环螯合剂4，11-双（羧甲基）-1，4，8，11-四氮杂双环[6.6.2]十六烷（CB-TE 2A）、1，4，7-三氮杂环壬烷、1-谷氨酸-4，7-乙酸（NODAGA）和DOTA偶联。在室温下制备Cu-64/nat-和Ga-68/nat-NODAGA-LM 3，并且在95 ℃下制备Cu-64/nat-CB-TE 2A-LM 3和Ga-68/nat-DOTA-LM 3。受体放射自显影和免疫荧光显微镜使用人胚肾（HEK）-sst 2细胞的结合亲和力和拮抗特性进行了测定。使用相同的细胞系评价体外内化和解离。用HEK-sst 2异种移植物进行生物分布和小动物PET研究。结果：所有金属肽均表现出拮抗作用。亲和力取决于螯合剂和放射性金属，变化约10倍; Ga-68/nat-NODAGA-LM 3具有最低的半最大抑制浓度（1.3 +/- 0.3 nmol/L）。生物分布研究显示在注射后1小时令人印象深刻的肿瘤摄取，特别是Cu-64-和Ga-68-NODAGA-LM 3（类似于每克组织40%注射剂量[%ID/g]），其被证明是特异性的。Cu-64-NODAGA-LM 3的背景清除快速且肿瘤洗脱相对缓慢（类似于15%ID/g，注射后24小时），Cu-64-CB-TE 2A-LM 3的背景清除几乎可忽略不计（分别为26.9 +/-3.3%ID/g和21.6 +/-2.1%ID/g，注射后4小时和24小时）。Cu-64-NODAGA-LM 3的肿瘤与正常组织的比率显著高于Cu-64-CB-TE 2-ALM 3（肿瘤与肾的比率，分别为12.8 +/- 3.6和1.7 +/- 0.3;肿瘤与肌肉的比率，分别为1，342 6 115和75.2 +/- 8.5，在24小时，P < 0.001）。小动物PET显示出清晰的肿瘤定位和高图像对比度，尤其是Cu-64-和Ga-68-NODAGA-LM 3。结论：这篇文章证明了基于生长抑素的放射性拮抗剂对螯合剂和放射性金属的亲和力和药代动力学的强烈依赖性。Cu-64-和Ga-68-NODAGA-LM 3和Cu-64-CB-TE 2A-LM 3是有希望的临床转化候选物，因为它们具有良好的药代动力学和PET扫描的高图像对比度。
Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-positive tumors, especially of subtype 2 (sst2). The clinically used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors determining the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four Cu-64 or Ga-68 radioantagonists for PET of sst2-positive tumors. Methods: The novel antagonist p-Cl-Phecyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (LM3) was coupled to 3 macrocyclic chelators, namely 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid (NODAGA), and DOTA. Cu-64/nat- and Ga-68/nat-NODAGA-LM3 were prepared at room temperature, and Cu-64/nat-CB-TE2A-LM3 and Ga-68/nat-DOTA-LM3 were prepared at 95 degrees C. Binding affinity and antagonistic properties were determined with receptor autoradiography and immunofluorescence microscopy using human embryonic kidney (HEK)-sst2 cells. In vitro internalization and dissociation was evaluated using the same cell line. Biodistribution and small-animal PET studies were performed with HEK-sst2 xenografts. Results: All metallopeptides demonstrated antagonistic properties. The affinities depend on chelator and radiometal and vary about 10-fold; Ga-68/nat-NODAGA-LM3 has the lowest half maximal inhibitory concentration (1.3 +/- 0.3 nmol/L). The biodistribution studies show impressive tumor uptake at 1 h after injection, particularly of Cu-64- and Ga-68-NODAGA-LM3 (similar to 40 percentage injected dose per gram of tissue [%ID/g]), which were proven to be specific. Background clearance was fast and the tumor washout relatively slow for Cu-64-NODAGA-LM3 (similar to 15 %ID/g, 24 h after injection) and almost negligible for Cu-64-CB-TE2A-LM3 (26.9 +/- 3.3 %ID/g and 21.6 +/- 2.1 %ID/g, 4 and 24 h after injection, respectively). Tumor-to-normal-tissue ratios were significantly higher for Cu-64-NODAGA-LM3 than for Cu-64-CB-TE2-ALM3 (tumor-to-kidney, 12.8 +/- 3.6 and 1.7 +/- 0.3, respectively; tumor-to-muscle, 1,342 6 115 and 75.2 +/- 8.5, respectively, at 24 h, P < 0.001). Small-animal PET shows clear tumor localization and high image contrast, especially for Cu-64- and Ga-68-NODAGA-LM3. Conclusion: This article demonstrates the strong dependence of the affinity and pharmacokinetics of the somatostatin-based radioantagonists on the chelator and radiometal. Cu-64- and Ga-68-NODAGA-LM3 and Cu-64-CB-TE2A-LM3 are promising candidates for clinical translation because of their favorable pharmacokinetics and the high image contrast on PET scans.