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

Abstract

Objective To synthesize 68Ga-1, 4, 7, 10-tetraazacyclododecane-N, N', N″, N-tetraacetic acid-D-Phe1-Tyr3-Thr8-octreotide (68Ga-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 68Ga-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 min 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 min. Results 68Ga-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, 68Ga-DOTATATE was synthesized within 30 min 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 min, and the labeling yield was over 99%. Three batches of the products were aseptic and pyrogen-free. In ICR mice, 68Ga-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 min postinjection and (0.78±0.32) %ID/g at 1 h. MicroPET imaging showed increased uptake of 68Ga-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 68Ga-DOTATATE could be successfully synthesized manually and automatically. The products reach to the specification of radioactive drugs and could be used as an attractive positron emitting radiotracer for detection of the somatostatin receptor-positive tumors. Key words: DOTATATE; Isotope labeling; Gallium radioisotopes; Chemical synthesis; Tomography, emission-computed; Mice, nude