Guo Zhide, Gao Mengna, Song Manli, Shi Changrong, Zhang Pu, Xu Duo, You Linyi, Zhuang Rongqiang, Su Xinhui, Liu Ting, Du Jin, Zhang Xianzhong
Department of Isotopes, China Institute of Atomic Energy, P. O. Box 2108, Beijing 102413, China.
Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiang'an South Rd, Xiamen 361102, China.
Molecules. 2016 Jun 22;21(6):817. doi: 10.3390/molecules21060817.
The folate receptor (FR) is overexpressed in a wide variety of human tumors. In our study, the multimeric concept was used to synthesize a dimeric folate derivative via a click reaction. The novel folate derivative (HYNIC-D₁-FA₂) was radiolabeled with (99m)Tc using tricine and trisodium triphenylphosphine-3,3',3″-trisulfonate (TPPTS) as coligands ((99m)Tc-HYNIC-D₁-FA₂) and its in vitro physicochemical properties, ex vivo biodistribution and in vivo micro-SPECT/CT imaging as a potential FR targeted agent were evaluated. It is a hydrophilic compound (log P = -2.52 ± 0.13) with high binding affinity (IC50 = 19.06 nM). Biodistribution in KB tumor-bearing mice showed that (99m)Tc-HYNIC-D₁-FA₂ had high uptake in FR overexpressed tumor and kidney at all time-points, and both of them could obviously be inhibited when blocking with free FA in the blocking studies. From the in vivo micro-SPECT/CT imaging results, good tumor uptake of (99m)Tc-HYNIC-D₁-FA₂ was observed in KB tumor-bearing mice and it could be blocked obviously. Based on the results, this new radiolabeled dimeric FA tracer might be a promising candidate for FR-targeting imaging with high affinity and selectivity.
叶酸受体（FR）在多种人类肿瘤中过表达。在我们的研究中，采用多聚体概念通过点击反应合成了一种二聚体叶酸衍生物。使用三（羟甲基）甲基甘氨酸和三苯基膦-3,3',3″-三磺酸钠（TPPTS）作为共配体，用（99m）Tc对新型叶酸衍生物（HYNIC-D₁-FA₂）进行放射性标记（（99m）Tc-HYNIC-D₁-FA₂），并评估了其体外物理化学性质、体内生物分布以及作为潜在的FR靶向剂的体内微型单光子发射计算机断层扫描/计算机断层扫描（micro-SPECT/CT）成像。它是一种亲水性化合物（log P = -2.52 ± 0.13），具有高结合亲和力（IC50 = 19.06 nM）。在荷KB肿瘤小鼠中的生物分布表明，（99m）Tc-HYNIC-D₁-FA₂在所有时间点在FR过表达的肿瘤和肾脏中摄取均较高，并且在阻断研究中用游离叶酸阻断时，两者的摄取均可明显受到抑制。从体内微型单光子发射计算机断层扫描/计算机断层扫描成像结果来看，在荷KB肿瘤小鼠中观察到（99m）Tc-HYNIC-D₁-FA₂对肿瘤有良好的摄取，并且其摄取可被明显阻断。基于这些结果，这种新的放射性标记二聚体叶酸示踪剂可能是一种具有高亲和力和选择性的FR靶向成像的有前景的候选物。
