Effects of the amino acid linkers on the melanoma-targeting and pharmacokinetic properties of 111In-labeled lactam bridge-cyclized alpha-MSH peptides.
Effects of the amino acid linkers on the melanoma-targeting and pharmacokinetic properties of 111In-labeled lactam bridge-cyclized alpha-MSH peptides.
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DOI：
10.2967/jnumed.110.086009
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Miao Y
中科院分区：
文献类型：
--
作者：
Guo H;Yang J;Gallazzi F;Miao Y
本研究的目的是研究氨基酸连接体对新型111in标记内酰胺桥式环化DOTA-[X]- cycmshhex{1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-[X]-c[asp - his - dph - arg - trp - lys]- conh2， X=GlyGlyNle， GlyGluNle或NleGlyGlu}肽的黑色素瘤靶向和药代动力学特性的深刻影响。设计并合成了3种新型多肽DOTA-GGNle-CycMSHhex、DOTA-GENle-CycMSHhex和DOTA-NleGE-CycMSHhex。在B16/F1黑色素瘤细胞中测定了肽的黑素皮质素-1 （MC1）受体结合亲和力。研究了111In-DOTA-GGNle-CycMSHhex和111In-DOTA-GENle-CycMSHhex在B16/F1黑色素瘤C57小鼠中的靶向性和药动学特性。DOTA-GGNle-CycMSHhex和DOTA-GENle-CycMSHhex的MC1受体结合亲和力分别为2.1和11.5 nM，而DOTA-NleGE-CycMSHhex的MC1受体结合亲和力为873.4 nM。- glygly -连接体的引入维持了黑色素瘤的高摄取，同时降低了肾脏和肝脏对111In-DOTA-GlyGlyNle-CycMSHhex的摄取。111In-DOTA-GGNle-CycMSHhex在注射后2和4 h的肿瘤摄取值分别为19.05±5.04和18.6±3.56%注射剂量/g （%ID/g）。111In-DOTA-GGNle-CycMSHhex在注射后2、4和24 h的肾脏摄取值分别比我们之前报道的111In-DOTA-Nle-CycMSHhex低28%、32%和42%，肝脏摄取值分别比111In-DOTA-Nle-CycMSHhex低61%、65%和68%。氨基酸连接体对111in标记的内酰胺桥环α-MSH肽的黑色素瘤靶向和药代动力学特性有深远的影响。- glygly -连接体的引入维持了黑色素瘤的高摄取，同时减少了肾脏和肝脏对111In-DOTA-GlyGlyNle-CycMSHhex的摄取，突出了其作为黑色素瘤检测的有效成像探针的潜力，以及当用治疗性放射性核素标记时用于黑色素瘤治疗的治疗肽。
The purpose of this study was to examine the profound effects of the amino acid linkers on the melanoma targeting and pharmacokinetic properties of novel 111In-labeled lactam bridge-cyclized DOTA-[X]-CycMSHhex {1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-[X]-c[Asp-His-dPhe-Arg-Trp-Lys]-CONH2, X=GlyGlyNle, GlyGluNle or NleGlyGlu} peptides. Three novel DOTA-GGNle-CycMSHhex, DOTA-GENle-CycMSHhex and DOTA-NleGE-CycMSHhex peptides were designed and synthesized. The melanocortin-1 (MC1) receptor binding affinities of the peptides were determined in B16/F1 melanoma cells. The melanoma targeting and pharmacokinetic properties of 111In-DOTA-GGNle-CycMSHhex and 111In-DOTA-GENle-CycMSHhex were determined in B16/F1 melanoma-bearing C57 mice. DOTA-GGNle-CycMSHhex and DOTA-GENle-CycMSHhex displayed 2.1 and 11.5 nM MC1 receptor binding affinities, whereas DOTA-NleGE-CycMSHhex showed 873.4 nM MC1 receptor binding affinity. The introduction of the -GlyGly- linker maintained high melanoma uptake while decreased the renal and liver uptakes of 111In-DOTA-GlyGlyNle-CycMSHhex. The tumor uptake values of 111In-DOTA-GGNle-CycMSHhex were 19.05 ± 5.04 and 18.6 ± 3.56 % injected dose/gram (%ID/g) at 2 and 4 h post-injection. 111In-DOTA-GGNle-CycMSHhex exhibited 28, 32 and 42% less renal uptake values than 111In-DOTA-Nle-CycMSHhex we reported previously, and 61, 65 and 68% less liver uptake values than 111In-DOTA-Nle-CycMSHhex at 2, 4 and 24 h post-injection, respectively. The amino acid linkers exhibited the profound effects on the melanoma targeting and pharmacokinetic properties of the 111In-labeled lactam bridge-cyclized α-MSH peptides. Introduction of the -GlyGly- linker maintained high melanoma uptake while reducing the renal and liver uptakes of 111In-DOTA-GlyGlyNle-CycMSHhex, highlighting its potential as an effective imaging probe for melanoma detection, as well as a therapeutic peptide for melanoma treatment when labeled with a therapeutic radionuclide.
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