用于黑色素瘤正电子发射断层显像（PET）的铜-64标记的内酰胺桥环化α-促黑素（α-MSH）肽
Cu-64-labeled lactam bridge-cyclized α-MSH peptides for PET imaging of melanoma.
作者信息
Guo Haixun, Miao Yubin
机构信息
College of Pharmacy, ‡Cancer Research and Treatment Center, and §Department of Dermatology, University of New Mexico , Albuquerque, New Mexico 87131, United States.
出版信息
Mol Pharm. 2012 Aug 6;9(8):2322-30. doi: 10.1021/mp300246j. Epub 2012 Jul 19.
The purpose of this study was to examine and compare the melanoma targeting and imaging properties of (64)Cu-NOTA-GGNle-CycMSH(hex) {(64)Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} and (64)Cu-DOTA-GGNle-CycMSH(hex) {(64)Cu-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 (64)Cu-NOTA-GGNle-CycMSH(hex) and (64)Cu-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 (64)Cu-NOTA-GGNle-CycMSH(hex). The tumor uptake of (64)Cu-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 (64)Cu-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 (64)Cu-NOTA-GGNle-CycMSHhex were 17.96, 16.95, and 8.02, whereas the tumor/kidney uptake ratios of (64)Cu-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 (64)Cu-NOTA-GGNle-CycMSH(hex) as compared to (64)Cu-DOTA-GGNle-CycMSH(hex). High melanoma uptake coupled with low accumulation in nontarget organs suggested (64)Cu-NOTA-GGNle-CycMSH(hex) as a lead radiolabeled peptide for melanoma imaging and therapy.
本研究的目的是检测并比较（64）Cu-NOTA-GGNle-CycMSH（hex）{（64）Cu-1,4,7-三氮杂环壬烷-1,4,7-三乙酸-Gly-Gly-Nle-c[天冬氨酸-组氨酸-D-苯丙氨酸-精氨酸-色氨酸-赖氨酸]-CONH2}和（64）Cu-DOTA-GGNle-CycMSH（hex）{（64）Cu-1,4,7,10-四氮杂环壬烷-1,4,7,10-四乙酸-GGNle-CycMSH（hex）}对黑色素瘤的靶向性和成像特性。使用芴甲氧羰基（Fmoc）化学合成了两种内酰胺桥环化肽，NOTA-GGNle-CycMSH（hex）和DOTA-GGNle-CycMSH（hex）。在B16/F1黑色素瘤细胞中测定了NOTA-GGNle-CycMSH（hex）的黑皮质素-1（MC1）受体结合亲和力，并与DOTA-GGNle-CycMSH（hex）进行比较。在荷B16/F1黑色素瘤的C57小鼠中测定了（64）Cu-NOTA-GGNle-CycMSH（hex）和（64）Cu-DOTA-GGNle-CycMSH（hex）的黑色素瘤靶向性和成像特性。NOTA-GGNle-CycMSH（hex）和DOTA-GGNle-CycMSH（hex）表现出相当的MC1受体结合亲和力（1.6对2.1 nM）。用NOTA替代DOTA显著增加了（64）Cu-NOTA-GGNle-CycMSH（hex）对黑色素瘤的摄取，并降低了其在肾脏和肝脏的摄取。注射后0.5、2和4小时，（64）Cu-NOTA-GGNle-CycMSH（hex）在肿瘤中的摄取为12.39±1.61至12.71±2.68% ID/g。注射后2、4和24小时，除肾脏外，（64）Cu-NOTA-GGNle-CycMSH（hex）在正常器官中的活性积累低于1.02% ID/g。（64）Cu-NOTA-GGNle-CycMSHhex的肿瘤/肝脏摄取比分别为17.96、16.95和8.02，而（64）Cu-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小时内，超过91%的注入放射性通过泌尿系统清除。与（64）Cu-DOTA-GGNle-CycMSH（hex）相比，用NOTA替代DOTA导致（64）Cu-NOTA-GGNle-CycMSH（hex）对黑色素瘤的摄取显著增加，而在非靶器官中的积累减少。黑色素瘤摄取高且在非靶器官中积累低表明（64）Cu-NOTA-GGNle-CycMSH（hex）是用于黑色素瘤成像和治疗的先导放射性标记肽。
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