Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Institute of Pharmaceutical Sciences, ETH Zurich, 8093, Zurich, Switzerland.
Mol Imaging Biol. 2013 Dec;15(6):649-54. doi: 10.1007/s11307-013-0651-x.
The folate receptor (FR) is a promising target for nuclear imaging due to its overexpression in many different cancer types. A drawback of using folate radioconjugates is the high accumulation of radioactivity in the kidneys. Therefore, the aim of this study was to develop a (18) F-labeled folate conjugate with an albumin-binding entity to enhance the blood circulation time and hence improve the tumor-to-kidney ratio.
The novel (18) F-folate was prepared by conjugation of a (18) F-labeled glucose azide to an alkyne-functionalized folate precursor containing an albumin-binding entity via Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radioconjugate was tested in vitro on FR-positive KB tumor cells and by biodistribution and positron emission tomography (PET) imaging studies using KB tumor-bearing mice.
The radiosynthesis of the albumin-binding [(18) F]fluorodeoxyglucose-folate ([(18) F]3) resulted in a radiochemical yield of 1-2 % decay corrected (d.c.) and a radiochemical purity of ≥95 %. The specific activity of [(18) F]3 ranged from 20 to 50 GBq/μmol. In vitro experiments revealed FR-specific binding of [(18) F]3 to KB tumor cells. In vivo we found an increasing uptake of [(18) F]3 into tumor xenografts over time reaching a value of ∼ 15 % injected dose (ID)/g at 4 h post-injection (p.i.). Uptake in the kidneys (∼ 13 % ID/g; 1 h p.i.) was approximately fourfold reduced compared to previously published (18) F-labeled folic acid derivatives. An excellent visualization of tumor xenografts with an unprecedentedly high tumor-to-kidney ratio (∼ 1) was obtained by PET imaging.
[(18) F]3 showed a favorable accumulation in tumor xenografts compared to the same folate conjugate without albumin-binding properties. Moreover, the increased tumor-to-kidney ratios improved the PET imaging quality significantly, in spite of a somewhat higher background radioactivity which was a consequence of the slower blood clearance of [(18) F]3.
叶酸受体（FR）在许多不同类型的癌症中过度表达，因此是核成像的一个有前途的靶点。使用叶酸放射性缀合物的一个缺点是放射性在肾脏中的大量积累。因此，本研究的目的是开发一种带有白蛋白结合物的（18）F 标记叶酸缀合物，以延长血液循环时间，从而提高肿瘤与肾脏的比值。
通过铜（I）催化的 1,3-偶极环加成反应，将（18）F 标记的葡萄糖叠氮化物与含有白蛋白结合物的炔基功能化叶酸前体连接，制备新型（18）F-叶酸。在 FR 阳性 KB 肿瘤细胞上进行体外测试，并通过 KB 荷瘤小鼠的生物分布和正电子发射断层扫描（PET）成像研究进行测试。
放射性合成白蛋白结合物[（18）F]氟脱氧葡萄糖叶酸[（18）F]3 的放射性化学产率为 1-2% 衰减校正（d.c.），放射性化学纯度≥95%。[（18）F]3 的比活度范围为 20-50GBq/μmol。体外实验表明[（18）F]3 与 KB 肿瘤细胞的 FR 特异性结合。在体内，我们发现[（18）F]3 随时间的推移逐渐进入肿瘤异种移植，在 4 小时后达到约 15% 注射剂量（ID）/g。与之前发表的（18）F 标记叶酸衍生物相比，肾脏摄取（约 13% ID/g；1 小时后）减少了约四倍。通过 PET 成像获得了肿瘤异种移植的极好可视化效果，肿瘤与肾脏的比值（约 1）前所未有。
与没有白蛋白结合特性的相同叶酸缀合物相比，[（18）F]3 在肿瘤异种移植中的积累更为有利。此外，尽管由于（18）F]3 的血液清除速度较慢而导致背景放射性略高，但肿瘤与肾脏的比值增加显著提高了 PET 成像质量。
