Kanazawa Masakatsu, Nishiyama Shingo, Hashimoto Fumio, Kakiuchi Takeharu, Tsukada Hideo
Central Research Laboratory, Hamamatsu Photonics K.K., 5000 Hirakuchi, Hamakita, Hamamatsu, Shizuoka, 434-8601, Japan.
EJNMMI Res. 2018 Jun 13;8(1):47. doi: 10.1186/s13550-018-0404-6.
The potential of the D-isomerization of 4-borono-2-F-fluoro-phenylalanine (F-FBPA) to improve its target tumor to non-target normal brain tissue ratio (TBR) was evaluated in rat brain glioma and compared with those of L- and D-C-methyl-tyrosine (C-CMT). The L- or D-isomer of F-FBPA was injected into rats through the tail vein, and their whole body kinetics and distributions were assessed using the tissue dissection method up to 90 min after the injection. The kinetics of L- and D-F-FBPA or L- and D-C-CMT in the C-6 glioma-inoculated rat brain were measured for 90 or 60 min, respectively, using high-resolution animal PET, and their TBRs were assessed.
Tissue dissection analyses showed that D-F-FBPA uptake was significantly lower than that of L-F-FBPA in the brain and abdominal organs, except for the kidney and bladder, reflecting the faster elimination rate of D-F-FBPA than L-F-FBPA from the blood to the urinary tract. PET imaging using F-FBPA revealed that although the brain uptake of D-F-FBPA was significantly lower than that of L-F-FBPA, the TBR of the D-isomer improved to 6.93 from 1.45 for the L-isomer. Similar results were obtained with PET imaging using C-CMT with a smaller improvement in TBR to 1.75 for D-C-CMT from 1.33 for L-C-CMT.
The present results indicate that D-F-FBPA is a better brain tumor imaging agent with higher TBR than its original L-isomer and previously reported tyrosine-based PET imaging agents. This improved TBR of D-F-FBPA without any pre-treatments, such as tentative blood-brain barrier disruption using hyperosmotic agents or sonication, suggests that the D-isomerization of BPA results in the more selective accumulation of B in tumor cells that is more effective and less toxic than conventional L-BPA.
在大鼠脑胶质瘤模型中评估了4-硼-2-氟苯丙氨酸（F-FBPA）的D-异构化对提高其靶肿瘤与非靶正常脑组织比值（TBR）的潜力，并与L-和D-C-甲基酪氨酸（C-CMT）进行比较。通过尾静脉将F-FBPA的L-或D-异构体注射到大鼠体内，并在注射后90分钟内使用组织解剖法评估其全身动力学和分布。使用高分辨率动物PET分别在接种C-6胶质瘤的大鼠脑中测量L-和D-F-FBPA或L-和D-C-CMT的动力学90分钟或60分钟，并评估其TBR。
组织解剖分析表明，除肾脏和膀胱外，D-F-FBPA在脑和腹部器官中的摄取明显低于L-F-FBPA，这反映了D-F-FBPA从血液到尿路的消除速度比L-F-FBPA快。使用F-FBPA的PET成像显示，虽然D-F-FBPA的脑摄取明显低于L-F-FBPA，但其D-异构体的TBR从L-异构体的1.45提高到了6.93。使用C-CMT的PET成像也得到了类似的结果，D-C-CMT的TBR从L-C-CMT的1.33略有提高至1.75。
目前的结果表明，D-F-FBPA是一种比其原始L-异构体和先前报道的基于酪氨酸的PET成像剂具有更高TBR的更好的脑肿瘤成像剂。D-F-FBPA无需任何预处理（如使用高渗剂或超声暂时破坏血脑屏障）即可提高TBR，这表明BPA的D-异构化导致B在肿瘤细胞中更具选择性的积累，比传统的L-BPA更有效且毒性更小。
