Synthesis and in vitro/in vivo evaluation of 99mTc-labeled folate conjugates for folate receptor imaging
Synthesis and in vitro/in vivo evaluation of 99mTc-labeled folate conjugates for folate receptor imaging
复制标题
用于叶酸受体成像的 99mTc 标记叶酸缀合物的合成和体外/体内评估
DOI：
10.1016/j.nucmedbio.2010.11.007
复制
发表时间：
2011-05-01
影响因子：
3.1
通讯作者：
Wang, Xuebin
中科院分区：
文献类型：
--
作者：
Lu, Jie;Pang, Yan;Wang, Xuebin
简介：叶酸受体（FR）是一个潜在的放射性核素显像的分子靶点，因为它在许多人上皮肿瘤细胞中过表达。在这项研究中，一种新的叶酸缀合物的合成和标记的Tc-99 m使用不同的共配体。方法：合成并表征了一种新的叶酸偶联物HYNIC-NHHN-FA。该偶联物分别用三羟甲基甘氨酸、三羟甲基甘氨酸/二苯基膦苯-3-磺酸钠（TPPMS）和三羟甲基甘氨酸/三苯基膦-3，3 '，3“-三磺酸三钠（TPPTS）作为共配体，用Tc-99 m进行放射性标记。通过高压液相色谱法（HPLC）纯化复合物。结果：用不同的配体标记99 m，得到3种配合物：Tc-99 m（HYNIC-NHHN-FA）（tricine），5，Tc-99 m（HYNIC-NHHN-FA）（tricine/TPPMS），6和Tc-99 m（HYNIC-NHHN-FA）（tricine/TPPTS），7。配合物5至少有两种异构体，经HPLC纯化后不稳定。配合物6和7在体外显示出高稳定性和与FR相似的亲和力。在荷KB肿瘤裸鼠体内的生物分布结果表明，配合物7在荷FR阳性肿瘤中有很高的摄取（注射后4 h为9.79= 1.66%ID/g），阻断实验结果证实了配合物7在体内的特异性蓄积。结论：共配体的修饰可以显著改变相应的99 m-HYNIC配合物的药代动力学性质。Tc-99 m（HYNIC-NHHN-FA）（tricine/TPPTS），7可能是FR成像的一种有前途的放射性示踪剂。(C)2011 Elsevier Inc. All rights reserved.
Introduction: Folate receptor (FR) is a potential molecular target for radionuclide imaging since it is overexpressed in many human epithelial tumor cells. In this study, a novel folate conjugate was synthesized and labeled with Tc-99m using different coligands. In vitro and in vivo evaluations of these complexes have been done to explore the effect of coligands on the stable, affinity and pharmacokinetic properties.Methods: A novel folate conjugate, HYNIC-NHHN-FA, was synthesized and characterized. This conjugate was radiolabeled with Tc-99m using tricine, tricine /diphenylphosphinobenzene-3-sulfonic acid sodium (TPPMS) and tricine /trisodium triphenylphosphine-3,3',3 ''-trisulfonate (TPPTS) as coligands, respectively. The complexes were purified by high-pressure liquid chromatography (HPLC). In vitro and in vivo evaluations were performed with FR-positive KB cells, normal Kunming mice and athymic nude mice bearing KB tumors.Results: Labeling with Tc-99m using different coligands resulted in three complexes, Tc-99m (HYNIC-NHHN-FA)(tricine), 5, Tc-99m (HYNIC-NHHN-FA)(tricine/TPPMS), 6 and Tc-99m (HYNIC-NHHN-FA)(tricine/TPPTS), 7. Complex 5 showed at least two isomers and was unstable after being purified by HPLC. Complexes 6 and 7 displayed high stability and similar affinity to FR in vitro. Biodistribution results in athymic nude mice bearing KB tumor showed that complex 7 had a high uptake in FR-positive tumor (9.79=/-1.66%ID/g at 4 h postinjection), and the results of blockade studies confirmed the specific accumulation of the radiotracer in vivo. However, complex 6 showed a low tumor uptake due to its fast excretion via the gastrointestinal tract.Conclusion: The modification of the coligands can significantly alter the pharmacokinetic properties of the corresponding Tc-99m-HYNIC complexes. Tc-99m (HYNIC-NHHN-FA)(tricine/TPPTS), 7 could be a promising radiotracer for FR imaging. (C) 2011 Elsevier Inc. All rights reserved.