Wang Hsin-Ell, Liao Ai-Ho, Deng Win-Ping, Chang Pi-Fang, Chen Jyh-Cheng, Chen Fu-Du, Liu Ren-Shen, Lee Jin-Shin, Hwang Jeng-Jong
Department of Medical Radiation Technology and Institute of Radiological Sciences, National Yang-Ming University, 155 Li-Nong Street, Section 2, Pei-tou, Taipei 112, Taiwan ROC.
J Nucl Med. 2004 Feb;45(2):302-8.
L-p-Boronophenylalanine (BPA) has been applied as a potential boron carrier for the treatment of malignant glioma in clinical boron neutron capture therapy (BNCT) since 1994. To provide the pharmacokinetics of BPA for clinical use of BNCT in Taiwan, 4-borono-2-(18)F-fluoro-L-phenylalanine-fructose ((18)F-FBPA-Fr) was synthesized and the biologic characteristics of this radiotracer in glioma-bearing rats were investigated.
Radiolabeled (18)F-F(2) was produced via the (20)Ne(d,alpha)(18)F reaction, and (18)F-acetyl hypofluorite ((18)F-AcOF) was generated by passing (18)F-F(2) through a column filled with tightly packed KOAc/HOAc powder. The effluent containing (18)F-AcOF was bubbled into BPA in trifluoroacetic acid, then purified by high-performance liquid chromatography, and further composited with fructose to afford (18)F-FBPA-Fr. Male Fischer 344 rats bearing F98 glioma in the left brain were used for biologic studies. The biodistribution of BPA-Fr and (18)F-FBPA-Fr was determined, and the microautoradiography and PET imaging of (18)F-FBPA-Fr were performed, on the 13th day after tumor inoculation.
The radiochemical purity of (18)F-FBPA-Fr was >97% and the radiochemical yield of (18)F-FBPA-Fr was 20%-25%. In glioma-bearing rats, the accumulation ratios of B-10 for glioma-to-normal brain were 2.05, 1.86, 1.24, and 1.10 at 0.5, 1, 2, and 4 h, respectively, after administration of 43 mg BPA-Fr via the tail vein. The accumulation ratios of (18)F-FBPA-Fr for glioma-to-normal brain were 3.45, 3.13, 2.61, and 2.02, whereas the tumor-to-heart blood ratios were 1.72, 2.61, 2.00, and 1.93, respectively, for the same time points. The uptake characteristics of BPA-Fr and (18)F-FBPA-Fr in F98 glioma were similar with a maximum at 1 h after the drugs' administration. The results obtained from the biodistribution studies indicated that 0.5-1 h after BPA-Fr injection would be the optimal time for BNCT. Biodistribution, PET images, and brain microautoradiography of (18)F-FBPA-Fr all confirmed this finding.
(18)F-FBPA-Fr showed specific tumor uptake in F98 glioma-bearing rats and could be used as a probe for BPA-Fr in BNCT. This study provides useful information for the future clinical application of BNCT in brain tumor therapy.
自1994年以来，L-对硼苯丙氨酸（BPA）作为一种潜在的硼载体，已应用于临床硼中子俘获疗法（BNCT）治疗恶性胶质瘤。为了提供BPA在台湾BNCT临床应用中的药代动力学，合成了4-硼-2-（18）F-氟-L-苯丙氨酸-果糖（（18）F-FBPA-Fr），并研究了这种放射性示踪剂在荷胶质瘤大鼠中的生物学特性。
通过（20）Ne（d，α）（18）F反应产生放射性标记的（18）F-F2，使（18）F-F2通过填充紧密的KOAc/HOAc粉末柱生成（18）F-乙酰次氟酸酯（（18）F-AcOF）。将含有（18）F-AcOF的流出物鼓泡到三氟乙酸中的BPA中，然后通过高效液相色谱法纯化，并进一步与果糖复合，得到（18）F-FBPA-Fr。将左脑荷F98胶质瘤的雄性Fischer 344大鼠用于生物学研究。在接种肿瘤后第13天，测定BPA-Fr和（18）F-FBPA-Fr的生物分布，并进行（18）F-FBPA-Fr的微观放射自显影和PET成像。
（18）F-FBPA-Fr的放射化学纯度>97%，（18）F-FBPA-Fr的放射化学产率为20%-25%。在荷胶质瘤大鼠中，经尾静脉注射43 mg BPA-Fr后，在0.5、1、2和4小时，胶质瘤与正常脑的硼-10积累比分别为2.05、1.86、1.24和1.10。在相同时间点，（18）F-FBPA-Fr的胶质瘤与正常脑积累比分别为3.45、3.13、2.61和2.02，而肿瘤与心脏血液比分别为1.72、2.61、2.00和1.93。BPA-Fr和（18）F-FBPA-Fr在F98胶质瘤中的摄取特征相似，给药后1小时达到最大值。生物分布研究结果表明，BPA-Fr注射后0.5-1小时是BNCT的最佳时间。（18）F-FBPA-Fr的生物分布、PET图像和脑微观放射自显影均证实了这一发现。
（18）F-FBPA-Fr在荷F98胶质瘤大鼠中显示出特异性肿瘤摄取，可作为BNCT中BPA-Fr的探针。本研究为BNCT在脑肿瘤治疗中的未来临床应用提供了有用信息。
