Watabe Tadashi, Hatazawa Jun
Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Hell J Nucl Med. 2015 Sep-Dec;18 Suppl 1:149.
(18)F-FDG-PET is used worldwide for oncology patients. However, we sometimes encounter false positive cases of (18)F-FDG PET, such as moderate uptake in the inflammatory lesion, because (18)F-FDG accumulates not only in the cancer cells but also in the inflammatory cells (macrophage, granulation tissue, etc). To overcome this limitation of (18)F-FDG, we started to use (4-borono-2- [(18)F]fluoro-L-phenylalanine) (18)F-FBPA, an artificial amino acid tracer which is focusing attention as a tumor specific PET tracer. Physiological accumulation of (18)F-FBPA is limited in the kidney and urinary tract in humans, which enable preferable evaluation of uptake in the abdominal organs compared to (11)C-methionine ((11)C-MET). The purpose of this study was to evaluate (18)F-FBPA as a tumor specific tracer by in vitro cellular uptake analysis focusing on the selectivity of L-type amino acid transporter 1 (LAT1), which is specifically expressed in tumor cells, and in vivo PET analysis in rat xenograft and inflammation models compared to (18)F-FDG and (11)C-methionine.
Uptake inhibition and efflux experiments were performed in HEK293-LAT1 and LAT2 cells using cold BPA, cold (18)F-FBPA, and hot (18)F-FBPA to evaluate LAT affinity and transport capacity. Position emission tomography studies were performed in rat xenograft model of C6 glioma 2 weeks after the implantation (n=9, body weight=197±10.5g) and subcutaneous inflammation model 4 days after the injection of turpentine oil (n=9, body weight=197±14.4g). Uptake on static PET images were compared among (18)F-FBPA at 60-70min post injection, (18)F-FDG at 60-70min, and (11)C-MET at 20-30min in the tumors and the inflammatory lesions by maximum standardized uptake value (SUVmax).
Cellular uptake analysis showed no significant difference in inhibitory effect and efflux of LAT1 between cold (18)F-FBPA and cold BPA, suggesting the same affinity and transport capacity via LAT1. Uptake of (18)F-FBPA via LAT1 was superior to LAT2 by the concentration dependent uptake analysis. Position emission tomography analysis using SUVmax showed significantly higher accumulation of (18)F-FDG in the tumor and the inflammatory lesions (7.19±2.11 and 4.66±0.63, respectively) compared to (18)F-FBPA (3.23±0.40 and 1.86±0.19, respectively) and (11)C-MET (3.39±0.43 and 1.63±0.11, respectively) (P<0.01 by Tukey test). No significant difference was observed between (18)F-FBPA and (11)C-MET.
(18)F-FBPA showed high selectivity of LAT1 by in vitro cellular uptake analysis, suggesting the potential as a tumor-specific substrate. In vivo PET analysis showed significantly lower uptake of (18)F-FBPA and (11)C-MET in the inflammatory lesions compared to (18)F-FDG, suggesting comparable utility of (18)F-FBPA PET to (11)C-MET PET in differentiating between the tumor and the inflammation.
（18）F - FDG - PET在全球范围内用于肿瘤患者。然而，我们有时会遇到（18）F - FDG PET的假阳性病例，例如炎症病变中的中等摄取，因为（18）F - FDG不仅在癌细胞中积累，还在炎症细胞（巨噬细胞、肉芽组织等）中积累。为了克服（18）F - FDG的这一局限性，我们开始使用（4 - 硼酰基 - 2 - [（18）F]氟 - L - 苯丙氨酸）（18）F - FBPA，一种作为肿瘤特异性PET示踪剂而受到关注的人工氨基酸示踪剂。（18）F - FBPA在人体肾脏和泌尿系统中的生理性积累有限，与（11）C - 蛋氨酸（（11）C - MET）相比，这使得对腹部器官摄取的评估更有利。本研究的目的是通过体外细胞摄取分析，重点关注在肿瘤细胞中特异性表达的L型氨基酸转运体1（LAT1）的选择性，以及与（18）F - FDG和（11）C - 蛋氨酸相比，在大鼠异种移植和炎症模型中的体内PET分析，来评估（18）F - FBPA作为肿瘤特异性示踪剂的情况。
使用冷BPA、冷（18）F - FBPA和热（18）F - FBPA在HEK293 - LAT1和LAT2细胞中进行摄取抑制和流出实验，以评估LAT亲和力和转运能力。在植入C6胶质瘤的大鼠异种移植模型（n = 9，体重 = 197±10.5g）植入后2周和注射松节油4天后的皮下炎症模型（n = 9，体重 = 197±14.4g）中进行正电子发射断层扫描研究。通过最大标准化摄取值（SUVmax）比较注射后60 - 70分钟的（18）F - FBPA、60 - 70分钟的（18）F - FDG和20 - 30分钟的（11）C - MET在肿瘤和炎症病变中的静态PET图像上的摄取情况。
细胞摄取分析显示冷（18）F - FBPA和冷BPA之间LAT1的抑制作用和流出无显著差异，表明通过LAT1具有相同的亲和力和转运能力。通过浓度依赖性摄取分析，（18）F - FBPA通过LAT1的摄取优于LAT2。使用SUVmax的正电子发射断层扫描分析显示，与（18）F - FBPA（分别为3.23±0.40和1.86±0.19）和（11）C - MET（分别为3.39±0.43和1.63±0.11）相比，（18）F - FDG在肿瘤和炎症病变中的积累显著更高（分别为7.19±2.11和4.66±0.63）（Tukey检验，P<0.01）。（18）F - FBPA和（11）C - MET之间未观察到显著差异。
体外细胞摄取分析表明（18）F - FBPA对LAT1具有高选择性，表明其作为肿瘤特异性底物的潜力。体内PET分析显示，与（18）F - FDG相比，（18）F - FBPA和（11）C - MET在炎症病变中的摄取显著更低，表明（18）F - FBPA PET在区分肿瘤和炎症方面与（11）C - MET PET具有相当的效用。
