Development of automatic synthesis of an androgen receptor imaging tracer for positron emission tomography

雄激素受体(AR)的表达是预测前列腺癌激素治疗后肿瘤反应的重要因素。16-氟-5-二氢睾酮(16β-[α；18&gt；F]FDHT)是AR显像剂的候选药物，但由于反应条件复杂，报道的方法难以采用自动化模块。在这项研究中，我们开发了一种使用塑料盒式自动PET放射性药物合成器自动合成[^&lt；18&gt；F]FDHT的方法。我们选择TRACERLab MXFDG(GE)作为[^&lt；18&gt；F]FDHT合成的模块，因为它具有灵活的编程能力，可以在无菌条件下接受盒式磁带布局的修改。通过改变前驱体和NaBH_4的用量、标记温度和时间、还原和水解等因素，研究了标记的最佳条件。最佳反应条件为：1、2、4 mg的16-τ-[[(三氟甲基)磺酰基]氧]-3，3-(乙二氧基)和…-1更多的7胜1负的腹肌。乙腈与干燥的氟化物一起在125℃下加热10min。所得溶液蒸发，然后在室温下用NaBH4在乙醇中还原。用0.1N盐酸灌胃15min。然后用Cosmosil 5C_&lt；18-AR-2，20 MMI进行制备高效液相色谱。D×250 mm，Nacalai Testque，50%乙腈/水，8.0ml/min，210 nm)。将所需的放射性部分收集到圆底烧瓶中，其中含有抗坏血酸钠作为自由基清除剂。在真空中除去溶剂，残留物溶解在10毫升的生理盐水中，然后通过无菌的0。22μm过滤器至无热原小瓶。NaBH_4还原反应在5分钟内完成。在RT条件下15min内不能完全水解，但在85℃时即可完成。最终产物放化产率为13.4±4.4%(n=7)。总合成时间不超过100min，包括制备高效液相色谱(HPLC)和注射剂的制备工艺。经小鼠急性毒性试验等质量控制，最终产品质量优良，适合临床研究。较少

Androgen receptor(AR) expression is an important factor to predict tumor responsiveness to hormonal therapy in prostate cancer. 16β-[^<18> F] fluoro-5α-dihydrotestosterone([^<18> F] FDHT) is a candidate for AR imaging PET radiopharmaceutical, however, the reported method was difficult to adopt an automatic modules because of the complex reaction conditions. In this study, we developed an automatic synthesis method for[^<18> F] FDHT using a plastic cassette-type automatic PET radiopharmaceutical synthesizer. We chose a TRACERlab MXFDG(GE) as the module for[^<18> F] FDHT synthesis because it has the flexibility programming and accepts modification to the cassette layout in aseptic condition. Optimum labeling condition was investigated by changing several factors(amount of precursor and NaBH_4, temperature and time of labeling, reduction and hydrolysis etc.) and the optimized condition is as follows : 1, 2 or 4 mg of 16τ-[[(trifluoromethyl) sulfonyl] oxy]-3, 3-(ethylenedioxy) and rostan-1 … More 7-one in abs. acetonitrile was heated at 125℃for 10 min with dried[^<18> F] fluoride. The resultant solution was evaporated, and then reduced with NaBH_4 in ethanol at room temperature. The hydrolysis with 0. 1N HCl was carried out for 15 min. Then the preparative HPLC was performed using a Cosmosil 5C_<18>-AR-2, 20 mmI. D. x 250 mm, Nacalai Tesque, 50% acetonitrile/water, 8. 0 ml/min, 210 nm) was performed. The desired radioactive fraction was collected to a round-bottom flask containing sodium ascorbate as a radical scavenger. The solvent was removed in vacuo and the residue was dissolved in 10 ml of saline, and then passed through a sterile 0. 22μm filter to a pyrogen-free vial. The reduction using NaBH_4 was completed in 5 min. The hydrolysis was inadequacy at RT in 15 min but it was accomplished at 85℃. The radiochemical yield in the final product was 13. 4±4. 4%(n 7). The total synthesis time including the preparative HPLC and the preparation process for an injection was less than 100 min. The quality control including acute toxicity test using mouse was confirmed that the final product was high quality and adapted for clinical research. Less