The present study describes modification of asparagine–glycine–arginine (NGR) peptide at N‐terminally and C‐terminally by introduction of a tridentate chelating scaffold via click chemistry reaction. The N‐terminal and C‐terminal modified peptides were radiometalated with [^99mTc(CO)₃]⁺ precursor. The influence of these moieties at the two termini on the targeting properties of NGR peptide was determined by in vitro cell uptake studies and in vivo biodistribution studies. The two radiolabeled constructs did not exhibit any significant variation in uptake in murine melanoma B16F10 cells during in vitro studies. In vivo studies revealed nearly similar tumor uptake of N‐terminally modified peptide construct 5 and C‐terminally construct 6 at 2 h p.i. (1.9 ± 0.1 vs 2.4 ± 0.2% ID/g, respectively). The tumor‐to‐blood (T/B) and tumor‐to‐liver (T/L) ratios of the two radiometalated peptides were also quite similar. The two constructs cleared from all the major organs (heart, lungs, spleen, stomach, and blood) at 4 h p.i. (<1% ID/g). Blocking studies carried out by coinjection of cCNGRC peptide led to approximately 50% reduction in the tumor uptake at 2 h p.i. This work thus illustrates the possibility of convenient modification/radiometalation of NGR peptide at either N‐ or C‐terminus without hampering tumor targeting and pharmacokinetics.

中文翻译：

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设计，合成和比较评估99m Tc（CO）3标记的N-末端和C-末端修饰的天冬酰胺-甘氨酸-精氨酸肽构建体。

本研究描述了通过点击化学反应引入三齿螯合支架在N端和C端修饰天冬酰胺-甘氨酸-精氨酸（NGR）肽的方法。用[ ^99m Tc（CO）₃ ] ⁺前体对N末端和C末端修饰的肽进行放射性金属化。通过体外细胞摄取研究和体内生物分布研究，确定了这些部分在两个末端对NGR肽的靶向特性的影响。在体外研究期间，这两种放射性标记的构建体在鼠类黑色素瘤B16F10细胞的摄取中未显示任何显着变化。体内研究显示，N末端修饰的肽构建体5和C末端构建体的肿瘤吸收几乎相似6在2小时的PI（1.9±0.1对2.4±0.2％ID / g时，分别地）。两种放射性金属肽的肿瘤血比（T / B）和肿瘤肝比（T / L）也非常相似。在感染后4小时（<1％ID / g）从所有主要器官（心脏，肺，脾脏，胃和血液）清除这两种构建体。通过共注射cCNGRC肽进行的阻断研究导致在pi 2 h肿瘤吸收减少约50％。这项工作因此说明了在N端或C端方便修饰/放射化NGR肽而不会影响肿瘤靶向和治疗的可能性。药代动力学。