Modification of the structure of a metallopeptide:: Synthesis and biological evaluation of 111In-labeled DOTA-conjugated rhenium-cyclized α-MSH analogues
Modification of the structure of a metallopeptide:: Synthesis and biological evaluation of 111In-labeled DOTA-conjugated rhenium-cyclized α-MSH analogues
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DOI：
10.1021/jm010408m
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发表时间：
2002-07-04
影响因子：
7.3
通讯作者：
Jurisson, SS
中科院分区：
文献类型：
--
作者：
Cheng, Z;Chen, JQ;Jurisson, SS
铼环化的CCMSH类似物是一种新型的黑色素瘤靶向金属肽，具有高的肿瘤摄取、长的肿瘤滞留时间和低的正常组织背景，是设计新型黑色素瘤靶向药物的理想结构基序。ReCCMSH已经用1，4，7，10-四氮杂环十二烷-1，4，7，10-四乙酸（DOTA）螯合物衍生化，使得其可以用多种放射性核素标记用于成像和治疗应用。本研究涉及通过修饰金属肽的结构来优化DOTA-ReCCMSH（S）的体内生物学性质。使用固相肽合成法，然后通过二环化合成了几种DOTA-ReCCMSH类似物Ac-Lys（DOTA）-ReCCMSH（4）DOTA-ReCCMSH（Arg（11））（6）、DOTA-ReCCMSH-OH（8）和DOTA-ReCCMSH-Asp-OH（10）。通过针对I-125-（Tyr（2））-NDP的竞争性结合测定来确定金属肽的IC 50值。用In-111对DOTA-β-环化肽进行放射性标记，在70 ℃下，在NH 4 OAc（0.1M; pH 5.5）缓冲溶液中进行30分钟。在0.01 M，pH 7.4，磷酸盐缓冲盐水/0.1%牛血清白蛋白溶液中评价放射性标记复合物的稳定性。通过反相高效液相色谱法将放射性标记的肽与未标记的肽分离后，在携带B16/F1鼠黑素瘤肿瘤的C57小鼠中进行放射性标记的复合物的生物分布。所有放射性标记的复合物显示快速血液清除（注射后2小时（pi）：In-111-S，0.07 +/- 0.03% ID/g; In-111-4，0.09 +/- 0.06% ID/g; In-111-6，0.21 +/- 0.08% ID/g; In-111-8，0.11 +/- 0.10% ID/g;和In-111-10，0.05 +/-0.03%ID/g），其清除主要通过尿液（4 h pi：In-111标记的S、4、6、8和10分别为93.5 +/- 1.7、87.8 +/- 6.5、89.8 +/- 4.2、93.3 +/- 1.1和93.8 +/- 1.8（% ID））。在注射后4小时，观察到In-111标记的S、4、6、8和10的肿瘤摄取值分别为9.45 +/- 0.90、6.01 +/- 2.36、17.41 +/-5，61、9.27 +/- 0.68和7.32 +/- 2.09（% ID/g）。In-111-S的肾脏摄取为9.27 +/- 2.65% ID/g，In-111-4为19.02 +/- 2.63% ID/g，In-111-6为7.37 +/- 1.13% ID/g，In-111-8为8.70 +/- 0.88% ID/g，In-111-10在4 h pi时为8.13 +/-1.47%ID/g。配合物6显示出比相应的Lys（11）类似物高的黑色素瘤摄取和较低的肾摄取，支持6作为潜在的治疗性放射性药物的进一步研究。
Rhenium-cyclized CCMSH analogues are novel melanoma-targeting metallopeptides with high tumor uptake, long tumor retention, and low background in normal tissues, which make these metallopeptides an ideal structural motif for designing novel melanoma-targeting agents. ReCCMSH has been derivatized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate so that it can be labeled with a wide variety of radionuclides for imaging and therapeutic applications. This study involved optimization of the in vivo biological properties of DOTA-ReCCMSH (S), through modification of the structure of the metallopeptide. Several DOTA-ReCCMSH analogues, Ac-Lys(DOTA)-ReCCMSH (4) DOTA-ReCCMSH(Arg(11)) (6), DOTA-ReCCMSH-OH (8), and DOTA-ReCCMSH-Asp-OH (10), were synthesized using solid phase peptide synthesis followed by rhenium cyclization. The IC50 values of the metallopeptides were determined through competitive binding assays against I-125-(Tyr(2))-NDP. Radiolabeling of the DOTA-rhenium-cyclized peptides with In-111 was carried out in NH4OAc (0.1 M; pH 5.5)-buffered solution for 30 min at 70 degreesC. The stability of the radiolabeled complexes was evaluated in 0.01 M, pH 7.4, phosphate-buffered saline/0.1% bovine serum albumin solution. After separation of the radiolabeled peptide from the unlabeled peptide by reverse phase high-performance liquid chromatography, the biodistribution of the radiolabeled complex was performed in C57 mice bearing B16/F1 murine melanoma tumors. All radiolabeled complexes showed fast blood clearance (2 h postinjection (pi): In-111-S, 0.07 +/- 0.03% ID/g; In-111-4, 0.09 +/- 0.06% ID/g; In-111-6, 0.21 +/- 0.08% ID/g; In-111-8, 0.11 +/- 0.10% ID/g; and In-111-10, 0.05 +/- 0.03% ID/g), and their clearance was predominantly through the urine (4 h pi: 93.5 +/- 1.7, 87.8 +/- 6.5, 89.8 +/- 4.2, 93.3 +/- 1.1, and 93.8 +/- 1.8 (% ID) for In-111-labeled S, 4, 6, 8, and 10, respectively). Tumor uptake values of 9.45 +/- 0.90, 6.01 +/- 2.36, 17.41 +/- 5,61, 9.27 +/- 0.68, and 7.32 +/- 2.09 (% ID/g) for In-111-labeled S, 4, 6, 8, and 10, respectively, were observed at 4 h pi. The kidney uptake was 9.27 +/- 2.65% ID/g for In-111-S, 19.02 +/- 2.63% ID/g for In-111-4, 7.37 +/- 1.13% ID/g for In-111-6, 8.70 +/- 0.88% ID/g for In-111-8, and 8.13 +/- 1.47% ID/g for In-111-10 at 4 h pi. Complex 6 showed high melanoma uptake and lower kidney uptake than the corresponding Lys(11) analogues, supporting 6 for further investigations as a potential therapeutic radiopharmaceutical.