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作为用于细菌感染成像的正电子发射断层显像（PET）示踪剂的[¹⁸F]标记麦芽糖衍生物的合成

Synthesis of [¹⁸F]-labelled maltose derivatives as PET tracers for imaging bacterial infection.

作者信息

Namavari Mohammad, Gowrishankar Gayatri, Hoehne Aileen, Jouannot Erwan, Gambhir Sanjiv S

机构信息

Molecular Imaging Program at Stanford, Departments of Radiology and Bioengineering, Bio-X Program, Stanford University, 318 Campus Dr., Clark Center E-150, Stanford, CA, USA.

出版信息

Mol Imaging Biol. 2015 Apr;17(2):168-76. doi: 10.1007/s11307-014-0793-5.

DOI:10.1007/s11307-014-0793-5
PMID:25277604
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4444077/
Abstract

PURPOSE

To develop novel positron emission tomography (PET) agents for visualization and therapy monitoring of bacterial infections.

PROCEDURES

It is known that maltose and maltodextrins are energy sources for bacteria. Hence, (18)F-labelled maltose derivatives could be a valuable tool for imaging bacterial infections. We have developed methods to synthesize 4-O-(α-D-glucopyranosyl)-6-deoxy-6-[(18)F]fluoro-D-glucopyranoside (6-[(18)F]fluoromaltose) and 4-O-(α-D-glucopyranosyl)-1-deoxy-1-[(18)F]fluoro-D-glucopyranoside (1-[(18)F]fluoromaltose) as bacterial infection PET imaging agents. 6-[(18)F]fluoromaltose was prepared from precursor 1,2,3-tri-O-acetyl-4-O-(2',3',-di-O-acetyl-4',6'-benzylidene-α-D-glucopyranosyl)-6-deoxy-6-nosyl-D-glucopranoside (5). The synthesis involved the radio-fluorination of 5 followed by acidic and basic hydrolysis to give 6-[(18)F]fluoromaltose. In an analogous procedure, 1-[(18)F]fluoromaltose was synthesized from 2,3, 6-tri-O-acetyl-4-O-(2',3',4',6-tetra-O-acetyl-α-D-glucopyranosyl)-1-deoxy-1-O-triflyl-D-glucopranoside (9). Stability of 6-[(18)F]fluoromaltose in phosphate-buffered saline (PBS) and human and mouse serum at 37 °C was determined. Escherichia coli uptake of 6-[(18)F]fluoromaltose was examined.

RESULTS

A reliable synthesis of 1- and 6-[(18)F]fluoromaltose has been accomplished with 4-6 and 5-8% radiochemical yields, respectively (decay-corrected with 95 % radiochemical purity). 6-[(18)F]fluoromaltose was sufficiently stable over the time span needed for PET studies (∼96% intact compound after 1-h and ∼65% after 2-h incubation in serum). Bacterial uptake experiments indicated that E. coli transports 6-[(18)F]fluoromaltose. Competition assays showed that the uptake of 6-[(18)F]fluoromaltose was completely blocked by co-incubation with 1 mM of the natural substrate maltose.

CONCLUSION

We have successfully synthesized 1- and 6-[(18)F]fluoromaltose via direct fluorination of appropriate protected maltose precursors. Bacterial uptake experiments in E. coli and stability studies suggest a possible application of 6-[(18)F]fluoromaltose as a new PET imaging agent for visualization and monitoring of bacterial infections.

摘要

目的

开发用于细菌感染可视化和治疗监测的新型正电子发射断层扫描（PET）剂。

程序

已知麦芽糖和麦芽糊精是细菌的能量来源。因此，（18）F标记的麦芽糖衍生物可能是用于细菌感染成像的有价值工具。我们已经开发出合成4-O-（α-D-吡喃葡萄糖基）-6-脱氧-6-[(18)F]氟-D-吡喃葡萄糖苷（6-[(18)F]氟麦芽糖）和4-O-（α-D-吡喃葡萄糖基）-1-脱氧-1-[(18)F]氟-D-吡喃葡萄糖苷（1-[(18)F]氟麦芽糖）作为细菌感染PET成像剂的方法。6-[(18)F]氟麦芽糖由前体1,2,3-三-O-乙酰基-4-O-（2',3'-二-O-乙酰基-4',6'-亚苄基-α-D-吡喃葡萄糖基）-6-脱氧-6- nosyl-D-葡萄糖苷（5）制备。合成过程包括5的放射性氟化，然后进行酸性和碱性水解以得到6-[(18)F]氟麦芽糖。按照类似的程序，由2,3,6-三-O-乙酰基-4-O-（2',3',4',6-四-O-乙酰基-α-D-吡喃葡萄糖基）-1-脱氧-1-O-三氟甲磺酰基-D-葡萄糖苷（9）合成1-[(18)F]氟麦芽糖。测定了6-[(18)F]氟麦芽糖在磷酸盐缓冲盐水（PBS）以及人和小鼠血清中于37°C下的稳定性。检测了大肠杆菌对6-[(18)F]氟麦芽糖的摄取。

结果

已分别以4 - 6%和5 - 8%的放射化学产率（经衰变校正，放射化学纯度为95%）成功合成了1-和6-[(18)F]氟麦芽糖。6-[(18)F]氟麦芽糖在PET研究所需的时间跨度内足够稳定（在血清中孵育1小时后约96%的完整化合物，2小时后约65%）。细菌摄取实验表明大肠杆菌能转运6-[(18)F]氟麦芽糖。竞争试验表明，与1 mM天然底物麦芽糖共同孵育可完全阻断6-[(18)F]氟麦芽糖的摄取。

结论

我们通过对适当保护的麦芽糖前体进行直接氟化成功合成了1-和6-[(1)F]氟麦芽糖。大肠杆菌中的细菌摄取实验和稳定性研究表明，6-[(18)F]氟麦芽糖有可能作为一种新型PET成像剂用于细菌感染的可视化和监测。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1552/4444077/d82653ba57b8/nihms687977f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1552/4444077/d82653ba57b8/nihms687977f8.jpg

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