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68Ga 标记的 exendin-3，一种用于 PET 检测胰岛素瘤的新型试剂。

68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET.

机构信息

Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

出版信息

Eur J Nucl Med Mol Imaging. 2010 Jul;37(7):1345-55. doi: 10.1007/s00259-009-1363-y. Epub 2010 Jan 29.

DOI:10.1007/s00259-009-1363-y
PMID:20111963
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2886138/
Abstract

PURPOSE: Insulinomas are neuroendocrine tumours derived from pancreatic beta-cells. The glucagon-like peptide 1 receptor (GLP-1R) is expressed with a high incidence (>90%) and high density in insulinomas. Glucagon-like peptide 1 (GLP-1), the natural ligand of GLP-1R, is rapidly degraded in vivo. A more stable agonist of GLP-1R is exendin-3. We investigated imaging of insulinomas with DOTA-conjugated exendin-3 labelled with (68)Ga. METHODS: Targeting of insulinomas with [Lys(40)(DOTA)]exendin-3 labelled with either (111)In or (68)Ga was investigated in vitro using insulinoma tumour cells (INS-1). [Lys(40)((111)In-DTPA)]Exendin-3 was used as a reference in this study. In vivo targeting was investigated in BALB/c nude mice with subcutaneous INS-1 tumours. PET imaging was performed using a preclinical PET/CT scanner. RESULTS: In vitro exendin-3 specifically bound and was internalized by GLP-1R-positive cells. In BALB/c nude mice with subcutaneous INS-1 tumours a high uptake of [Lys(40)((111)In-DTPA)]exendin-3 in the tumour was observed (33.5 +/- 11.6%ID/g at 4 h after injection). Uptake was specific, as determined by coinjection of an excess of unlabelled [Lys(40)]exendin-3 (1.8 +/- 0.1%ID/g). The pancreas also exhibited high and specific uptake (11.3 +/- 1.0%ID/g). High uptake was also found in the kidneys (144 +/- 24%ID/g) and this uptake was not receptor-mediated. In this murine tumour model optimal targeting of the GLP-1R expressing tumour was obtained at exendin doses < or =0.1 microg. Remarkably, tumour uptake of (68)Ga-labelled [Lys(40)(DOTA)]exendin-3 was lower (8.9 +/- 3.1%ID/g) than tumour uptake of (111)In-labelled [Lys(40)(DTPA)]exendin-3 (25.4 +/- 7.2%ID/g). The subcutaneous tumours were clearly visualized by small-animal PET imaging after injection of 3 MBq of [Lys(40)((68)Ga-DOTA)]exendin-3. CONCLUSION: [Lys(40)((68)Ga-DOTA)]Exendin-3 specifically accumulates in insulinomas, although the uptake is lower than that of [Lys(40)((111)In-DTPA)]exendin-3. Therefore, [Lys(40)((68)Ga-DOTA)]exendin-3 is a promising tracer to visualize insulinomas with PET.

摘要

目的：胰岛素瘤是源自胰岛β细胞的神经内分泌肿瘤。胰高血糖素样肽 1 受体 (GLP-1R) 在胰岛素瘤中表达具有高发生率 (>90%)和高密度。GLP-1 是 GLP-1R 的天然配体，在体内迅速降解。GLP-1R 的一种更稳定的激动剂是 exendin-3。我们研究了用 DOTA 缀合的 exendin-3 标记的 (68)Ga 对胰岛素瘤的成像。

方法：使用胰岛素瘤肿瘤细胞 (INS-1) 在体外研究了用 (111)In 或 (68)Ga 标记的 [Lys(40)(DOTA)]exendin-3 的靶向性。在这项研究中，[Lys(40)((111)In-DTPA)]Exendin-3 被用作参考。在皮下植入 INS-1 肿瘤的 BALB/c 裸鼠中进行体内靶向研究。使用临床前 PET/CT 扫描仪进行 PET 成像。

结果：体外实验中，外源性 exendin-3 特异性结合并被 GLP-1R 阳性细胞内化。在皮下植入 INS-1 肿瘤的 BALB/c 裸鼠中，观察到 [Lys(40)((111)In-DTPA)]exendin-3 在肿瘤中的高摄取 (注射后 4 小时为 33.5 +/- 11.6%ID/g)。通过共注射过量未标记的 [Lys(40)]exendin-3 (1.8 +/- 0.1%ID/g) 确定摄取是特异性的。胰腺也表现出高特异性摄取 (11.3 +/- 1.0%ID/g)。肾脏也有高摄取 (144 +/- 24%ID/g)，但这种摄取不是受体介导的。在这种小鼠肿瘤模型中，外源性 exendin-3 的最佳靶向剂量小于或等于 0.1 微克。值得注意的是，(68)Ga 标记的 [Lys(40)(DOTA)]exendin-3 的肿瘤摄取率 (8.9 +/- 3.1%ID/g) 低于 (111)In 标记的 [Lys(40)(DTPA)]exendin-3 的肿瘤摄取率 (25.4 +/- 7.2%ID/g)。注射 3MBq [Lys(40)((68)Ga-DOTA)]exendin-3 后，通过小动物 PET 成像可以清楚地观察到皮下肿瘤。

结论：[Lys(40)((68)Ga-DOTA)]Exendin-3 特异性积聚在胰岛素瘤中，尽管摄取量低于 [Lys(40)((111)In-DTPA)]exendin-3。因此，[Lys(40)((68)Ga-DOTA)]exendin-3 是一种有前途的示踪剂，可用于 PET 可视化胰岛素瘤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/740ee90e76c0/259_2009_1363_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/b414755163a3/259_2009_1363_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/4726fac1f519/259_2009_1363_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/b59df47c999f/259_2009_1363_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/2fbae648cdb4/259_2009_1363_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/f4f3f530618a/259_2009_1363_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/d6f593acc080/259_2009_1363_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/d6ed50b91099/259_2009_1363_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/4020d8321ef6/259_2009_1363_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/740ee90e76c0/259_2009_1363_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/b414755163a3/259_2009_1363_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/4726fac1f519/259_2009_1363_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/b59df47c999f/259_2009_1363_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/2fbae648cdb4/259_2009_1363_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/f4f3f530618a/259_2009_1363_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/d6f593acc080/259_2009_1363_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/d6ed50b91099/259_2009_1363_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/4020d8321ef6/259_2009_1363_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1649/2886138/740ee90e76c0/259_2009_1363_Fig9_HTML.jpg

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