Namavari Mohammad, Gowrishankar Gayatri, Srinivasan Ananth, Gambhir Sanjiv S, Haywood Thomas, Beinat Corinne
Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bioengineering Bio-X Program, Stanford University, Stanford, California, USA.
J Labelled Comp Radiopharm. 2018 May 15;61(5):408-414. doi: 10.1002/jlcr.3601. Epub 2018 Mar 30.
The aim of this study was to develop a positron emission tomography (PET) tracer to visualize and monitor therapeutic response to bacterial infections. In our continued efforts to find maltose based PET tracers that can image bacterial infections, we have designed and prepared 6''-[ F]fluoromaltotriose as a second generation PET imaging tracer targeting the maltodextrin transporter of bacteria. We have developed methods to synthesize 6''-deoxy-6''-[ F]fluoro-α-D-glucopyranosyl-(1-4)-O-α-D-glucopyranosyl-(1-4)-O-D-glucopyranose (6''-[ F]-fluoromaltotriose) as a bacterial infection PET imaging agent. 6''-[ F]fluoromaltotriose was prepared from precursor, 2'',3'',4''-tri-O-acetyl-6''-O-nosyl-α-D-glucopyranosyl-(1-4)-O-2',3',6'-tri-O-acetyl-α-D-glucopyranosyl-(1-4)-1,2,3,6-tetra-O-acetyl-D-glucopyranose (per-O-acetyl-6''-O-nosyl-maltotriose 4). This method utilizes the reaction between precursor 4 and anhydrous [ F]KF/Kryptofix 2.2.2 in dimethylformamide (DMF) at 85°C for 10 minutes to yield per-O-acetyl-6''-deoxy-6-'' [ F]-fluoromaltotriose (7). Successive acidic and basic hydrolysis of the acetyl protecting groups in 7 produced 6''-[ F]fluoromaltotriose (8). Also, cold 6''- [ F]fluoromaltotriose was prepared from per-O-acetyl-6''-hydroxymaltotriose via a diethylaminosulfur trifluoride reaction followed by a basic hydrolysis. A successful synthesis of 6''-[ F]-fluoromaltotriose has been accomplished in 8 ± 1.2% radiochemical yield (decay corrected). Total synthesis time was 120 minutes. Serum stability of 6''-[ F]fluoromaltotriose at 37°C indicated that 6''-[ F]-fluoromaltotriose remained intact up to 2 hours. In conclusion, we have successfully synthesized 6''-[ F]-fluoromaltotriose via direct fluorination of an appropriate precursor of a protected maltotriose.
本研究的目的是开发一种正电子发射断层扫描（PET）示踪剂，以可视化和监测对细菌感染的治疗反应。在我们持续努力寻找可对细菌感染进行成像的基于麦芽糖的PET示踪剂的过程中，我们设计并制备了6''-[F]氟麦芽三糖，作为靶向细菌麦芽糖糊精转运蛋白的第二代PET成像示踪剂。我们已开发出合成6''-脱氧-6''-[F]氟-α-D-吡喃葡萄糖基-(1-4)-O-α-D-吡喃葡萄糖基-(1-4)-O-D-吡喃葡萄糖（6''-[F]-氟麦芽三糖）的方法，将其作为细菌感染PET成像剂。6''-[F]氟麦芽三糖由前体2'',3'',4''-三-O-乙酰基-6''-O-亚硝基-α-D-吡喃葡萄糖基-(1-4)-O-2',3',6'-三-O-乙酰基-α-D-吡喃葡萄糖基-(1-4)-1,2,3,6-四-O-乙酰基-D-吡喃葡萄糖（全-O-乙酰基-6''-O-亚硝基麦芽三糖4）制备而成。该方法利用前体4与无水[F]KF/穴醚2.2.2在二甲基甲酰胺（DMF）中于85°C反应10分钟，生成全-O-乙酰基-6''-脱氧-6-''[F]-氟麦芽三糖（7）。7中乙酰保护基的连续酸水解和碱水解产生了6''-[F]氟麦芽三糖（8）。此外，通过二乙氨基三氟化硫反应，随后进行碱水解，由全-O-乙酰基-6''-羟基麦芽三糖制备了冷的6''-[F]氟麦芽三糖。已成功合成6''-[F]-氟麦芽三糖，放射化学产率为8±1.2%（衰变校正）。总合成时间为120分钟。6''-[F]氟麦芽三糖在37°C下的血清稳定性表明，6''-[F]-氟麦芽三糖在长达2小时内保持完整。总之，我们通过对受保护麦芽三糖的合适前体进行直接氟化，成功合成了6''-[F]-氟麦芽三糖。
