Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
Nucl Med Biol. 2011 May;38(4):557-65. doi: 10.1016/j.nucmedbio.2010.11.007. Epub 2011 Feb 4.
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 (99m)Tc 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.
A novel folate conjugate, HYNIC-NHHN-FA, was synthesized and characterized. This conjugate was radiolabeled with (99m)Tc 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.
Labeling with (99m)Tc using different coligands resulted in three complexes, (99m)Tc (HYNIC-NHHN-FA)(tricine), 5, (99m)Tc (HYNIC-NHHN-FA)(tricine/TPPMS), 6 and (99m)Tc (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.
The modification of the coligands can significantly alter the pharmacokinetic properties of the corresponding (99m)Tc-HYNIC complexes. (99m)Tc (HYNIC-NHHN-FA)(tricine/TPPTS), 7 could be a promising radiotracer for FR imaging.
叶酸受体（FR）是放射性核素成像的潜在分子靶标，因为它在许多人类上皮肿瘤细胞中过度表达。在这项研究中，合成了一种新型叶酸缀合物，并使用不同的配位体用（99m）Tc 标记。已经对这些复合物进行了体外和体内评估，以探讨配位体对稳定、亲和力和药代动力学性质的影响。
合成并表征了一种新型叶酸缀合物 HYNIC-NHHN-FA。该缀合物分别使用三羧酸、三羧酸/二苯膦苯-3-磺酸酸钠（TPPMS）和三羧酸/三（对甲苯磺酰基）膦（TPPTS）作为配位体用（99m）Tc 标记。复合物通过高压液相色谱（HPLC）纯化。使用 FR 阳性 KB 细胞、正常昆明小鼠和荷 KB 肿瘤的裸鼠进行体外和体内评价。
使用不同配位体用（99m）Tc 标记导致三种复合物，（99m）Tc（HYNIC-NHHN-FA）（三羧酸），5、（99m）Tc（HYNIC-NHHN-FA）（三羧酸/TPPMS），6 和（99m）Tc（HYNIC-NHHN-FA）（三羧酸/TPPTS），7。复合物 5 显示至少两种异构体，并用 HPLC 纯化后不稳定。复合物 6 和 7 在体外显示出与 FR 相似的高稳定性和亲和力。荷 KB 肿瘤的裸鼠体内分布结果表明，复合物 7 在 FR 阳性肿瘤中有高摄取（注射后 4 小时为 9.79±1.66%ID/g），阻断研究结果证实了体内放射性示踪剂的特异性积累。然而，由于其通过胃肠道快速排泄，复合物 6 显示出低肿瘤摄取。
配位体的修饰可以显著改变相应的（99m）Tc-HYNIC 复合物的药代动力学性质。（99m）Tc（HYNIC-NHHN-FA）（三羧酸/TPPTS），7 可能是 FR 成像的一种有前途的放射性示踪剂。
