Cu-64-Labeled Lactam Bridge-Cyclized α-MSH Peptides for PET Imaging of Melanoma
Cu-64-Labeled Lactam Bridge-Cyclized α-MSH Peptides for PET Imaging of Melanoma
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DOI：
10.1021/mp300246j
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发表时间：
2012-08-01
影响因子：
4.9
通讯作者：
Miao, Yubin
中科院分区：
文献类型：
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作者：
Guo, Haixun;Miao, Yubin
本研究的目的是检查和比较Cu-64-NOTA-GGNle-CycMSH（hex）{Cu-64- 1，4，7-三氮杂环壬烷-1，4，7-三乙酸-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH 2}和Cu-64-DOTA-GGNle-CycMSH（hex）{Cu-64- 1，4，7，10-四氮杂环壬烷-1，4，7，10-四乙酸-GGNle-CycMSH（hex）}的黑色素瘤靶向和成像性质。使用芴基甲氧基羰基（Fmoc）化学合成两种内酰胺桥环化肽，NOTA-GGNle-CycMSH（hex）和DOTA-GGNle-CycMSH（hex）。在B16/F1黑素瘤细胞中测定NOTA-GGNle-CycMSH（hex）的黑皮质素-1（MC 1）受体结合亲和力，并与DOTA-GGNle-CycMSH（hex）进行比较。在携带B16/F1黑素瘤的C57小鼠中测定Cu-64-NOTA-GGNle-CycMSH（hex）和Cu-64-DOTA-GGNle-CycMSH（hex）的黑素瘤靶向和成像性质。NOTA-GGNle-CycMSH（hex）和DOTA-GGNle-CycMSH（hex）显示出相当的MC 1受体结合亲和力（1.6 vs 2.1 nM）。用NOTA取代DOTA显著增加了黑色素瘤摄取，并降低了Cu-64-NOTA-GGNle-CycMSH（hex）的肾和肝摄取。在注射后0.5、2和4小时，Cu-64-NOTA-GGNle-CycMSH（hex）的肿瘤摄取在12.39 +/-1.61至12.71 +/-2.68%ID/g之间。Cu-64-NOTA-GGNle-CycMSH（hex）活性在正常器官中的累积低于1.02%ID/g，但在注射后2、4和24 h的肾脏除外。Cu-64-NOTA-GGNle-CycMSH（hex）的肿瘤/肝脏摄取比分别为17.96、16.95和8.02，而Cu-64-NOTA-GGNle-CycMSH（hex）的肿瘤/肾脏摄取比在注射后2、4和24小时分别为2.52、3.60和5.74。注射后2 h，超过91%的注射放射性通过泌尿系统清除。与Cu-64-DOTAGGNle-CycMSH（hex）相比，NOTA取代DOTA导致黑色素瘤摄取的显著增加以及Cu-64-NOTA-GGNle-CycMSH（hex）的肾和肝摄取的降低。黑色素瘤高摄取加上非靶器官中的低积累表明Cu-64-NOTA-GGNle-CycMSH（hex）作为黑色素瘤成像和治疗的先导放射性标记肽。
The purpose of this study was to examine and compare the melanoma targeting and imaging properties of Cu-64-NOTA-GGNle-CycMSH(hex) {Cu-64-1,4,7-triazacyclononane-1,4,7-triacetic acid-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} and Cu-64-DOTA-GGNle-CycMSH(hex) {Cu-64-1,4,7,10-tetraazacyclononane-1,4,7,10-tetraacetic acid-GGNle-CycMSH(hex)}. Two lactam bridge-cyclized peptides, NOTA-GGNle-CycMSH(hex) and DOTA-GGNle-CycMSH(hex) were synthesized using fluorenylmethyloxy carbonyl (Fmoc) chemistry. The melanocortin-1 (MC1) receptor binding affinity of NOTA-GGNle-CycMSH(hex) was determined in B16/F1 melanoma cells and compared with DOTA-GGNle-CycMSH(hex). The melanoma targeting and imaging properties of Cu-64-NOTA-GGNle-CycMSH(hex) and Cu-64-DOTA-GGNle-CycMSH(hex) were determined in B16/F1 melanoma-bearing C57 mice. NOTA-GGNle-CycMSH(hex) and DOTA-GGNle-CycMSH(hex) displayed comparable MC1 receptor binding affinities (1.6 vs 2.1 nM). The substitution of DOTA with NOTA dramatically increased the melanoma uptake and decreased the renal and liver uptake of Cu-64-NOTA-GGNle-CycMSH(hex). The tumor uptake of Cu-64-NOTA-GGNle-CycMSH(hex) was between 12.39 +/- 1.61 and 12.71 +/- 2.68% ID/g at 0.5, 2, and 4 h postinjection. The accumulation of Cu-64-NOTA-GGNle-CycMSH(hex) activity in normal organs was lower than 1.02% ID/g except for the kidneys 2, 4, and 24 h postinjection. The tumor/liver uptake ratios of Cu-64-NOTA-GGNle-CycMSH(hex) were 17.96, 16.95, and 8.02, whereas the tumor/kidney uptake ratios of Cu-64-NOTA-GGNle-CycMSH(hex) were 2.52, 3.60, and 5.74 at 2, 4, and 24 h postinjection, respectively. Greater than 91% of the injected radioactivity cleared through the urinary system by 2 h postinjection. The substitution of DOTA with NOTA resulted in a dramatic increase in melanoma uptake and decrease in renal and liver uptake of Cu-64-NOTA-GGNle-CycMSH(hex) as compared to Cu-64-DOTAGGNle-CycMSH(hex). High melanoma uptake coupled with low accumulation in nontarget organs suggested Cu-64-NOTA-GGNle-CycMSH(hex) as a lead radiolabeled peptide for melanoma imaging and therapy.