Evaluation of a 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid-Conjugated Bombesin-Based Radioantagonist for the Labeling with Single-Photon Emission Computed Tomography, Positron Emission Tomography, and Therapeutic Radionuclides
Evaluation of a 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid-Conjugated Bombesin-Based Radioantagonist for the Labeling with Single-Photon Emission Computed Tomography, Positron Emission Tomography, and Therapeutic Radionuclides
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DOI：
10.1158/1078-0432.ccr-08-3145
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发表时间：
2009-08-15
影响因子：
11.5
通讯作者：
Maecke, Helmut R.
中科院分区：
文献类型：
--
作者：
Mansi, Rosalba;Wang, Xuejuan;Maecke, Helmut R.
目的：G蛋白偶联受体激动剂被用作放射性标记载体，用于肿瘤的体内定位和治疗。最近，基于生长抑素的拮抗剂显示出优于激动剂的上级效果。在这里，我们比较了新的[In-111/Ga-68]-标记的蛙皮素为基础的拮抗剂RM 1与激动剂[In-111]-AMBA靶向胃泌素释放肽受体（GRPR）。实验设计：IC 50，Kd值，和拮抗剂效力使用PC-3和HEK-GRPR细胞测定。在移植有PC-3肿瘤的裸鼠中进行生物分布和成像研究。结果：[In-nat]-RM 1的IC 50值为14 +/-3.4 nmol/L，与对照组相比，[In-nat]-RM 1的IC 50值为14 +/- 3.4 nmol/L，与对照组相比，[In-nat]-RM 1的IC 50值为14 +/- 3.4 nmol/L。发现[In-nat/111]-RM 1与GRPR结合的Kd为8.5 +/- 2.7 nmol/L，而[In-111]-AMBA的Kd为0.6 +/- 0.3 nmol/L。与[In-111]-AMBA（0.7 +/- 0.1 nmol/L）相比，观察到[In-111]-RM 1（2.4 +/-0.2 nmol/L）的最大结合位点数值更高。[Lu-nat]-AMBA在基于免疫荧光的内化测定中是有效的激动剂，而[In-nat]-RM 1单独无活性，但有效地拮抗蛙皮素效应。这些数据通过钙释放测定证实。药代动力学显示放射性拮抗剂在高肿瘤摄取方面具有优势（注射后4小时为13.4 +/- 0.8% IA/g vs 3.69 +/- 0.75% IA/g）。结论：[In-111/68 Ga]-RM 1与[In-111]-AMBA相比，具有较低的GRPR亲和力，但仍具有较好的上级靶向性。如针对生长抑素受体靶向放射肽所发现的，基于GRP的放射性拮抗剂似乎在体内成像和潜在地还在GRPR阳性肿瘤的靶向放射治疗方面优于放射性激动剂上级。(Clin Cancer Res 2009;15（16）：5240-9）
Purpose: G protein-coupled receptor agonists are being used as radiolabeled vectors for in vivo localization and therapy of tumors. Recently, somatostatin-based antagonists were shown to be superior to agonists. Here, we compare the new [In-111/Ga-68]-labeled bombesin-based antagonist RM1 with the agonist [In-111]-AMBA for targeting the gastrin-releasing peptide receptor (GRPR).Experimental Design: IC50, K-d values, and antagonist potency were determined using PC-3 and HEK-GRPR cells. Biodistribution and imaging studies were done in nude mice transplanted with the PC-3 tumor. The antagonist potency was assessed by evaluating the effects on calcium release and on receptor internalization monitored by immunofluorescence microscopy.Results: The IC50 value of [In-nat]-RM1 was 14 +/- 3.4 nmol/L. [In-nat/111]-RM1 was found to bind to the GRPR with a K-d of 8.5 +/- 2.7 nmol/L compared with a K-d of 0.6 +/- 0.3 nmol/L of [In-111]-AMBA. A higher maximum number of binding site value was observed for [In-111]-RM1 (2.4 +/- 0.2 nmol/L) compared with [In-111]-AMBA(0.7 +/- 0.1 nmol/L). [Lu-nat]-AMBA is a potent agonist in the immunofluorescence-based internalization assay, whereas [In-nat]-RM1 is inactive alone but efficiently antagonizes the bombesin effect. These data are confirmed by the calcium release assay. The pharmacokinetics showed a superiority of the radioantagonist with regard to the high tumor uptake (13.4 +/- 0.8% IA/g versus 3.69 +/- 0.75% IA/g at 4 hours after injection. as well as to all tumor-to-normal tissue ratios.Conclusion: Despite their relatively low GRPR affinity, the antagonists [In-111/68 Ga]-RM1 showed superior targeting properties compared with [In-111]-AMBA. As found for somatostatin receptor-targeting radiopeptides, GRP-based radioantagonists seem to be superior to radioagonists for in vivo imaging and potentially also for targeted radiotherapy of GRPR-positive tumors. (Clin Cancer Res 2009;15(16):5240-9)