Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor.
Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor.
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通过锡前体用放射性碘和 211At 标记的糖基化奥曲酸类似物的合成和评估。
DOI：
10.1021/bc0502560
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发表时间：
2006
影响因子：
4.7
通讯作者：
Zalutsky,MR
中科院分区：
文献类型：
--
作者：
Vaidyanathan,G;Affleck,DJ;Schottelius,M;Wester,H;Friedman,HS;Zalutsky,MR
3-奥曲肽(TOC)N-末端的碳水化和C-末端的苏氨酸取代了TOC的C-末端的苏氨酸残基，改善了其放射性碘化衍生物的药代动力学和肿瘤靶向性。然而，由于一碘酪氨酸(MIT)与甲状腺激素的相似性，这些多肽非常容易在体内脱碘。这项工作的目标是开发同时包含糖部分和非酪氨酸假体基团的八曲酸酯类似物，在该基团上可以引入放射性碘或211 At。固相合成和随后的修饰提供了目标peptideNα-(1-deoxy-d-fructosyl)-Nε-(3-iodobenzoyl)-Lys0-octreotate的碘标准(GIBLO)和相应的TiN precursorNα-(1-deoxy-d-fructosyl)-Nε-[(3-tri-n-butylstannyl)benzoyl]-Lys0-octreotate(GTBLO)。GIBLO取代了生长抑素受体亚型2(SSTR2)阳性的AR42J大鼠胰腺肿瘤细胞膜上的[125I]TOC，IC50为0.46±0.05 nM，表明GIBLO与SSTR2保持亲和力。[~(131)I]~(131)GIBLO([~(211)At]andNα-(1-deoxy-d-fructosyl)-Nε-(3-[211At]astatobenzoyl)-Lys0-octreotate)的放化产率分别为21.2±4.9%和46.8±9.5%。从D341Med髓母细胞瘤细胞的双标记内化试验中，[131I]GIBLO的最大比内化放射性为输入剂量的1.78±0.8%，而[125I]I-Gluc-TocA的最大比内化放射性为9.67±0.43%forNα-(1-deoxy-d-fructosyl)-[125I]iodo-Tyr3-octreotate。在4h内，[~(131)I]GIBLO和[~(211)At]GABLO在该细胞系中的内化程度相似。在D341小鼠皮下移植瘤中，0.5h、1h和4h对[125I]I-Gluc-Toca的摄取分别为21.5±4.0%ID/g、18.8±7.7%ID/g和0.9±0.4%ID/g。与之相比，[131I]GIBLO的这些值分别为6.9±1.2%ID/g、4.7±1.4%ID/g和0.8±0.5%ID/g。综上所述，尽管GIBLO保持了对SSTR2的亲和力，但它在体外和体内的肿瘤摄取显著低于I-Gluc-TocA，这表明其他因素，如净电荷和肽的整体几何形状可能是重要的。
Carbohydration of N-terminus and substitution of a threonine for the threoninol residue at the C-terminus of Tyr3-octreotide (TOC) has resulted in improved pharmacokinetics and tumor targeting of its radioiodinated derivatives. Yet, these peptides are very susceptible to in vivo deiodination due to the similarity of monoiodotyrosine (MIT) to thyroid hormone. The goal of this work was to develop octreotate analogues containing both a sugar moiety and a nontyrosine prosthetic group on which a radioiodine or211At can be introduced. Solid-phase synthesis and subsequent modifications delivered an iodo standard of the target peptideNα-(1-deoxy-d-fructosyl)-Nε-(3-iodobenzoyl)-Lys0-octreotate (GIBLO) and the corresponding tin precursorNα-(1-deoxy-d-fructosyl)-Nε-[(3-tri-n-butylstannyl)benzoyl]-Lys0-octreotate (GTBLO). GIBLO displaced [125I]TOC from somatostatin receptor subtype 2 (SSTR2)-positive AR42J rat pancreatic tumor cell membranes with an IC50of 0.46 ± 0.05 nM suggesting that GIBLO retained affinity to SSTR2. GTBLO was radiohalogenated to [131I]GIBLO andNα-(1-deoxy-d-fructosyl)-Nε-(3-[211At]astatobenzoyl)-Lys0-octreotate ([211At]GABLO) in 21.2 ± 4.9% and 46.8 ± 9.5% radiochemical yields, respectively. From a paired-label internalization assay using D341 Med medulloblastoma cells, the maximum specific internalized radioactivity from [131I]GIBLO was 1.78 ± 0.8% of input dose compared to 9.67 ± 0.43% forNα-(1-deoxy-d-fructosyl)-[125I]iodo-Tyr3-octreotate ([125I]I-Gluc-TOCA). Over a 4 h period, the extent of internalization of [131I]GIBLO and [211At]GABLO was similar in this cell line. In D341 Med murine subcutaneous xenografts, the uptake of [125I]I-Gluc-TOCA at 0.5, 1 and 4 h was 21.5 ± 4.0% ID/g, 18.8 ± 7.7% ID/g, and 0.9 ± 0.4% ID/g, respectively. In comparison, these values for [131I]GIBLO were 6.9 ± 1.2% ID/g, 4.7 ± 1.4% ID/g, and 0.8 ± 0.5% ID/g. Both in vitro and in vivo catabolism studies did not suggest the severance of the lys0along with its appendages from the peptide. Taken together, although GIBLO maintained affinity to SSTR2, its tumor uptake both in vitro and in vivo was substantially lower than that of I-Gluc-TOCA suggesting other factors such as net charge and overall geometry of the peptide may be important.