Synthesis and Preclinical Evaluation of Novel ^99mTc-Labeled FR-Targeting Agents with Satisfactory Imaging Contrast and Reduced Renal Uptake

The folate receptor is overexpressed in a variety of epithelial-derived malignant cells. Several folate-based tracers have shown the ability to target FR, but excessive renal uptake is a general concern. To decrease renal uptake and achieve high target-to-nontarget ratios, two folate derivatives (DProFA and DAlaFA) were designed and synthesized. Eight complexes with high labeling yields and good in vitro stability were obtained by radiolabeling with technetium-99m and different coligands. The results of both in vitro cell and in vivo normal mice biodistribution studies demonstrated specific binding of eight complexes to the FR. Among them, [99mTc]Tc-DProFA-L1 exhibited lower off-target uptake and high tumor uptake in tumor-bearing mice, and significant inhibition in the biodistribution and SPECT/CT imaging study. The lower renal uptake of [99mTc]Tc-DProFA-L1 may prevent irradiation damage to the kidney. Consequently, [99mTc]Tc-DProFA-L1 is a highly promising candidate probe for the diagnosis of epithelial tumors in clinical nuclear medicine.叶酸受体（folate receptor）在多种上皮来源的恶性细胞中呈过表达状态。多款叶酸基显像剂已被证实可靶向叶酸受体（FR），但肾脏摄取过量是这类显像剂普遍存在的共性问题。为降低肾脏摄取并实现较高的靶/非靶比值，研究人员设计并合成了两种叶酸衍生物：DProFA与DAlaFA。通过以锝-99m与不同协同配体进行放射性标记，成功获得8种标记产率优异、体外稳定性良好的配合物。体外细胞实验与正常小鼠体内生物分布研究的结果均证实，该8种配合物可与叶酸受体特异性结合。其中，[99mTc]Tc-DProFA-L1在荷瘤小鼠体内展现出更低的非靶组织摄取与较高的肿瘤摄取水平，且在生物分布与SPECT/CT成像研究中表现出显著的靶向抑制效果。[99mTc]Tc-DProFA-L1较低的肾脏摄取特性可有效避免肾脏遭受辐射损伤。综上，[99mTc]Tc-DProFA-L1是一款极具临床应用潜力的上皮肿瘤诊断显像探针，适用于临床核医学领域。