68Ga—DOTATATE的合成及动物实验研究

Synthesis and in vivo evaluation of 68Ga-DOTATATE in mice

目的研究金属核素多功能模块自动化及手工合成68Ga．1，4，7，10-四氮杂十二烷-N，N，N，N-四乙酸-D-苯丙氨酸1-酪氨酸3-苏氨酸墙-奥曲肽（68Ga—DOTATATE）的可行性，并探讨其生物学分布及肿瘤显像特点。方法采用强阳离子交换（SCX）柱金属核素多功能模块自动化及手工方法合成68Ga—DOTATATE，并对产品注射液进行质量控制。取ICR小鼠30只，分为5组，分别于注射68Ga—DOTATATE后10、30、60、120和240min处死，取各脏器、称质量并测定放射性计数，计算放射性摄取值（％ID／g），观察生物学分布。对荷AR42J大鼠胰腺外分泌腺肿瘤裸鼠注射68Ga—DOTATATE后行microPET显像，观察肿瘤对68Ga．DOTATATE的摄取情况。结果金属核素多功能模块自动化与手工合成2种方法均能顺利合成68Ga—DOTATATE。产品均为无色澄明溶液，pH值为6．5±0．1，放化纯均大于99％，室温放置4h仍大于99％。自动化合成需时约30min，放化产率为（51．8±3．2）％（时间衰减校正）；手工合成需时约20min，标记率大于99％。14d细菌培养及细菌内毒素检查结果均符合规定。ICR小鼠体内生物学分布结果显示，肾脏为药物排泄器官，肝、脾、胰腺和肾上腺摄取较高，肌肉软组织摄取低；药物的血液清除陕，10rain为（4．41±0．81）％ID／g，1h时仅为（O．78±0．32）％ID／g。荷AR42J瘤裸鼠microPET显像示，肿瘤组织对68Ga．DOTATATE明显高摄取，T／NT分别为2．01±0．29（10min）、6．74±2．90（30min）和4．46＋2．05（60min）。结论68Ga—DOTATATE合成工艺简单、质控合格、动物实验结果良好，是一种有潜在应用前景的新型生长抑素类特异性正电子显像剂。

Objective To synthesize 68Ga-1,4,7,10-tetraazacyclododecane-N,N＇,N＇,N＇-tetraacetic acid-D-Phel-Tyr3-ThrS-octreotide （68 Ga-DOTATATE） manually and automatically, validate its qualities in vitro, and evaluate its biodistribution in ICR mice and the microPET imaging in nude mice bearing pancreatic AR42J tumor. Methods 68 Ga-DOTATATE was synthesized by automatic method using commercial metal isotope multifunctional module with strong cation exchange （SCX） column and by manual method. Both the products were measured for quality control. For the biodistribution study 5 groups of ICR mice were injected with 68Ga-DOTATATE（ 1.11 MBq） and executed at 10, 30, 60, 120 and 240 rain postinjection, respectively. The organs were weighted, and %ID/g was calculated. Nude mice bearing pancreatic AR42J tumor were intravenously injected with 3.7 MBq 68Ga-DOTATATE, and then microPET imaging was acquired at 10, 30, 60, 120, 18 and 240 rain. Results 6SGa-DOTATATE could be successfully synthesized by the automatic and manual methods. Both the product injections were colorless and clear. The pH value was 6.5±0.1. For the products obtained from the two methods, the radiochemical purities were over 99%,and the products were stable for 4 h at room temperature. For the automatic method, 6s Ga-DOTATATE was synthesized within 30 rain and with the radiochemical yield of （51.8±3.2）% （time decay corrected） . For the manual method, the time used for the synthesis was 20 rain, and the labeling yield was over 99%. Three batches of the products were aseptic and pyrogen-free. In ICR mice, 6SGa-DOTATATE was excreted by the kidney, and showed relatively high accumulation in the liver, spleen, pancreas and adrenal glands, while lower in the bone and soft tissue. The clearance from blood was fast with （4.41±0.81） %ID/g at 10 rain postinjection and （0.78±0.32） % ID/g at 1 h. MicroPET imaging showed increased uptake of 6SGa- DOTATATE in the tumor tissues, and T/NT were 2.01±0.29（ 10 min）, 6.74±2.90（30 min） and 4.46± 2. 05 （60 min）, respectively. Conclusions 6s Ga-DOTATATE could be successfully synthesized manually and automatically. The products reach to the specification of radioactive drugs and could be used as an at- tractive positron emitting radiotracer for detection of the somatostatin receptor-positive tumors.