基于叶酸的新型 PET 放射性示踪剂的开发： ⁶⁸Ga-DOTA-叶酸缀合物的临床前评估。
Development of new folate-based PET radiotracers: preclinical evaluation of ⁶⁸Ga-DOTA-folate conjugates.
机构信息
Division of Radiological Chemistry, University Hospital Basel, 4031, Basel, Switzerland.
出版信息
Eur J Nucl Med Mol Imaging. 2011 Jan;38(1):108-19. doi: 10.1007/s00259-010-1597-8. Epub 2010 Aug 27.
PURPOSE
A number of (111)In- and (99m)Tc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A (68)Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of (68)Ga from a generator. The aim of the study was to develop a new (68)Ga-folate-based PET radiotracer.
METHODS
Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propylamine as a spacer, respectively. Both conjugates were labelled with (67/68)Ga. Binding affinity, internalization and externalization studies were performed using the FR-positive KB cell line. Biodistribution and PET/CT imaging studies were performed in nude mice, on a folate-deficient diet, bearing KB and HT1080 (FR-negative) tumours, concurrently. The new radiotracers were evaluated comparatively to the reference molecule (111)In-DTPA-folate ((111)In-P3139).
RESULTS
The K(d) values of (67/68)Ga-P3026 (4.65 ± 0.82 nM) and (67/68)Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order (67/68)Ga-P3026 > (67/68)Ga-P1254 > (111)In-P3139, while almost double cellular retention was found for (67/68)Ga-P3026 and (67/68)Ga-P1254, compared to (111)In-P3139. The biodistribution data of (67/68)Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to (111)In-P3139. PET/CT images, performed with (68)Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours.
CONCLUSION
The DOTA-folate conjugates can be efficiently labelled with (68)Ga in labelling yields and specific activities which allow clinical application. The characteristics of the (67/68)Ga-DOTA-folates are comparable to (111)In-DTPA-folate, which has already been used in clinical trials, showing that the new conjugates are promising candidates as PET radiotracers for FR-positive tumours.
目的
许多（111）In-和（99m）Tc-叶酸基示踪剂已被评估为成像叶酸受体（FR）阳性肿瘤的诊断剂。（68）Ga-叶酸基放射性药物将非常有趣，结合了 PET 技术的优势和从发生器获得（68）Ga 的可用性。本研究的目的是开发一种新的（68）Ga-叶酸基 PET 放射性示踪剂。
方法
使用 1,2-二氨基乙烷和 3-[2-[2-（3-氨基丙氧基）-乙氧基]-乙氧基]-丙胺分别合成了两种新的 DOTA-叶酸缀合物，命名为 P3026 和 P1254。两种缀合物均用（67/68）Ga 标记。使用 FR 阳性 KB 细胞系进行结合亲和力、内化和外化研究。在同时患有叶酸缺乏饮食的 FR 阴性 KB 和 HT1080（FR 阴性）肿瘤的裸鼠中进行了生物分布和 PET/CT 成像研究。将新的放射性示踪剂与参考分子（111）In-DTPA-叶酸（（111）In-P3139）进行了比较评估。
结果
（67/68）Ga-P3026（4.65±0.82 nM）和（67/68）Ga-P1254（4.27±0.42 nM）的 Kd 值表明对 FR 具有高亲和力。内化率遵循（67/68）Ga-P3026>（67/68）Ga-P1254>（111）In-P3139 的顺序，而与（111）In-P3139 相比，（67/68）Ga-P3026 和（67/68）Ga-P1254 的细胞内保留率几乎增加了一倍。（67/68）Ga-DOTA-叶酸的生物分布数据显示，FR 阳性肿瘤和肾脏的摄取量高且受体介导，与（111）In-P3139 相比无显著差异。使用（68）Ga-P3026 进行的 PET/CT 图像显示肾脏摄取量高，FR 阳性肿瘤清晰可见。
结论
DOTA-叶酸缀合物可以以允许临床应用的标记产率和比活度有效地用（68）Ga 标记。（67/68）Ga-DOTA-叶酸的特性与已在临床试验中使用的（111）In-DTPA-叶酸相当，表明新的缀合物是 FR 阳性肿瘤的 PET 放射性示踪剂的有前途的候选物。
Zotero 插件