[10B]硼剂和用于药代动力学评估的核成像探针构成了成功的硼中子捕获疗法 (BNCT) 的基本组合。然而，临床BNCT中使用的4-[10B]硼-L-苯丙氨酸（BPA）具有不良的水溶性和肿瘤选择性。因此，我们合成了氟化和α-甲基化的3-硼-L-苯丙氨酸（3BPA）衍生物，以实现改善的水溶性、肿瘤靶向性和生物分布。所有 3BPA 衍生物的水溶性均比 BPA 高 10 倍以上。用 α-甲基化 3BPA 衍生物处理可导致细胞通过 L 型氨基酸转运蛋白 (LAT) 2 的摄取减少，同时保持 LAT1 识别，从而显着提高 LAT1/LAT2 选择性。生物分布研究表明，氟化 α-甲基 3BPA 衍生物可减少非目标组织（包括肌肉、皮肤和血浆）中的硼积累。因此，与 3BPA 和 BPA 相比，这些衍生物显示出显着改善的肿瘤与正常组织的比率。总体而言，氟化 α-甲基 3BPA 衍生物与相应的放射性氟化化合物具有作为未来 BNCT/PET 治疗诊断学的有前景药物的潜力。版权所有 © 2023 Elsevier Inc. 保留所有权利。

A [10B]boron agent and a nuclear imaging probe for pharmacokinetic estimation form the fundamental pair in successful boron neutron capture therapy (BNCT). However, 4-[10B]borono-l-phenylalanine (BPA), used in clinical BNCT, has undesirable water solubility and tumor selectivity. Therefore, we synthesized fluorinated and α-methylated 3-borono-l-phenylalanine (3BPA) derivatives to realize improved water solubility, tumor targetability, and biodistribution. All 3BPA derivatives exhibited over 10 times higher water solubility than BPA. Treatment with α-methylated 3BPA derivatives resulted in decreased cell uptake via l-type amino acid transporter (LAT) 2 while maintaining LAT1 recognition, thereby significantly improving LAT1/LAT2 selectivity. Biodistribution studies showed that fluorinated α-methyl 3BPA derivatives exhibited reduced boron accumulation in nontarget tissues, including muscle, skin, and plasma. Consequently, these derivatives demonstrated significantly improved tumor-to-normal tissue ratios compared to 3BPA and BPA. Overall, fluorinated α-methyl 3BPA derivatives with the corresponding radiofluorinated compounds hold potential as promising agents for future BNCT/PET theranostics.Copyright © 2023 Elsevier Inc. All rights reserved.