Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China.
Bioorg Med Chem. 2009 Nov 1;17(21):7510-6. doi: 10.1016/j.bmc.2009.09.017. Epub 2009 Sep 15.
Asialoglycoprotein receptors (ASGP-R) are well known to exist on the mammalian liver, situate on the surface of hepatocyte membrane. Quantitative imaging of asialoglycoprotein receptors could estimate the function of the liver. (99m)Tc labeled galactosyl-neoglycoalbumin (NGA) and diethylenetriaminepentaacetic acid galactosyl human serum albumin (GSA) have been developed for SPECT imaging and clinical used in Japan. In this study, we labeled the NGA with (18)F to get a novel PET tracer [(18)F]FNGA and evaluated its hepatic-targeting efficacy and pharmacokinetics.
NGA was labeled with (18)F by conjugation with N-succinimidyl-4-(18)F-fluorobenzoate ([(18)F]SFB) under a slightly basic condition. The in vivo metabolic stability of [(18)F]FNGA was determined. Ex vivo biodistribution of [(18)F]FNGA and blocking experiment was investigated in normal mice. MicroPET images were acquired in rat with and without block at 5 min and 15 min after injection of the radiotracer (3.7MBq/rat), respectively.
Starting with (18)F(-) Kryptofix 2.2.2./K(2)CO(3) solution, the total reaction time for [(18)F]FNGA is about 150 min. Typical decay-corrected radiochemical yield is about 8-10%. After rapid purified with HiTrap desalting column, the radiochemical purity of [(18)F]FNGA was more than 99% determined by radio-HPLC. [(18)F]FNGA was metabolized to produce [(18)F]FB-Lys in urine at 30 min. Ex vivo biodistribution in mice showed that the liver accumulated 79.18+/-7.17% and 13.85+/-3.10% of the injected dose per gram at 5 and 30 min after injection, respectively. In addition, the hepatic uptake of [(18)F]FNGA was blocked by pre-injecting free NGA as blocking agent (18.55+/-2.63%ID/g at 5 min pi), indicating the specific binding to ASGP receptor. MicroPET study obtained quality images of rat at 5 and 15 min post-injection.
The novel ASGP receptor tracer [(18)F]FNGA was synthesized with high radiochemical yield. The promising biological properties of [(18)F]FNGA afford potential applications for assessment of hepatocyte function in the future. It may provide quantitative information and better resolution which particularly help to the liver surgery.
评价新型 ASGP 受体（ASGP-R）显像剂[18F]FNGA 的体内生物学特性，为其进一步临床应用提供实验依据。
以 N-琥珀酰亚胺基-4-[18F]氟苯甲酸（[18F]SFB）为标记试剂，在弱碱性条件下与 N-乙酰基-D-氨基葡萄糖（NGA）进行标记反应，制备[18F]FNGA。采用高效液相色谱（HPLC）法测定其放射化学纯度，测定其在正常小鼠体内的代谢稳定性，观察其在正常小鼠体内的生物分布及其特异性摄取。
以[18F]氟-氟化钾为原料，经亲核取代反应制备[18F]FNGA，总反应时间约为 150 min，放化产率为 8%～10%，经高效液相色谱（HPLC）法纯化后，其放射化学纯度大于 99%。在正常小鼠体内实验中，注射后 30 min 时，尿液中可检测到放射性代谢产物[18F]FB-Lys。放射性药物在肝脏的摄取在注射后 5 min 和 30 min 时分别达到 79.18%±7.17%ID/g和 13.85%±3.10%ID/g。进一步的阻断实验显示，注射游离 NGA 作为阻断剂后，肝脏摄取明显下降（5 min 时为 18.55%±2.63%ID/g），表明[18F]FNGA 与 ASGP-R 具有特异性结合。
成功制备了新型 ASGP-R 显像剂[18F]FNGA，其具有良好的体内生物学特性，有望用于评估肝细胞的功能，为临床应用提供实验依据。
