School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
Nucl Med Biol. 2011 Jan;38(1):121-7. doi: 10.1016/j.nucmedbio.2010.06.009. Epub 2010 Aug 16.
[(18)F]BAY94-9172 (Florbetaben) (Compound 8) is a positron emission tomography (PET) tracer that is currently in Phase III study for in vivo mapping of fibrillar amyloid β as a pathological hallmark for Alzheimer's disease. This work reports new methods for the synthesis of [(19)F]BAY94-9172 and its two different precursors and radiosynthesis of [(18)F]BAY94-9172 with the two precursors by purification using Sep-Pak cartridge.
The reference standard [(19)F]BAY94-9172 and the new precursor (Compound 9) were obtained from the reactions of (E)-4-methylamino-4'-hydroxystilbene (Compound 1) with methanesulfonic acid 2-[2-(2-fluoro-ethoxy)-ethoxy]-ethyl ester (Compound 11) and methanesulfonic acid 2-[2-(2-methanesulfonyloxy-ethoxy)-ethoxy]-ethyl ester (Compound 13), respectively. The reported precursor (Compound 6) is an N-BOC-protected mesylate compound, which was obtained from Compound 9. The one-step radiosynthesis of [(18)F]BAY94-9172 was carried out in the modified PET-MF-2V-IT-1 synthesizer by [(18)F]fluorination of the new precursor (Compound 9) and purification with plus C18 Sep-Pak cartridges and was compared with two-step one-pot radiosynthesis using the reported precursor (Compound 6) and Sep-Pak cartridge purification.
For one-step radiosynthesis, the uncorrected radiochemical yield of [(18)F]BAY94-9172 was 23 ± 3% (n = 5, based on [(18)F]fluoride) within 30 min and the radiochemical purity was greater than 95%. For two-step one-pot radiosynthesis, the uncorrected radiochemical yield of [(18)F]BAY94-9172 was 17 ± 2% in 45 min (n = 4, based on [(18)F]fluoride) with the radiochemical purity being above 95% after the Sep-Pak cartridge purification.
[(19)F]BAY94-9172 and the two precursors were synthesized by a short synthetic route. Compared with HPLC purification, the use of Sep-Pak purification of [(18)F]BAY94-9172 reduced the total radiosynthesis time. The one-step radiosynthesis of [(18)F]BAY94-9172 is convenient and can easily be applied to the commercial PET tracer synthesizer for automated synthesis.
[(18)F]BAY94-9172（Florbetaben）（化合物 8）是一种正电子发射断层扫描（PET）示踪剂，目前正在进行 III 期研究，用于体内映射纤维状淀粉样 β，作为阿尔茨海默病的病理标志。这项工作报道了合成[(18)F]BAY94-9172 及其两种不同前体的新方法，以及通过使用 Sep-Pak 小柱对两种前体进行纯化来进行[(18)F]BAY94-9172 的放射性合成。
参考标准[(19)F]BAY94-9172 和新前体（化合物 9）是通过（E）-4-甲氨基-4'-羟基二苯乙烯（化合物 1）与甲磺酸 2-[2-（2-氟乙氧基）-乙氧基]-乙基酯（化合物 11）和甲磺酸 2-[2-（2-甲磺酰氧基乙氧基）-乙氧基]-乙基酯（化合物 13）的反应获得的。报道的前体（化合物 6）是一种 N-BOC 保护的甲磺酸酯化合物，它是从化合物 9 获得的。[(18)F]BAY94-9172 的一步法放射性合成是在改良的 PET-MF-2V-IT-1 合成器中进行的，通过新前体（化合物 9）的[(18)F]氟化和使用 plus C18 Sep-Pak 小柱进行纯化，并与使用报道的前体（化合物 6）和 Sep-Pak 小柱纯化的两步一锅法放射性合成进行了比较。
对于一步法放射性合成，在 30 分钟内，未校正的[(18)F]BAY94-9172 的放射性化学产率为 23±3%（n=5，基于[(18)F]氟化物），放射性化学纯度大于 95%。对于两步一锅法放射性合成，在 45 分钟内，[(18)F]BAY94-9172 的未校正放射性化学产率为 17±2%（n=4，基于[(18)F]氟化物），经 Sep-Pak 小柱纯化后，放射性化学纯度大于 95%。
通过短的合成路线合成了[(19)F]BAY94-9172 和两种前体。与 HPLC 纯化相比，使用 Sep-Pak 纯化[(18)F]BAY94-9172 可缩短总放射性合成时间。[(18)F]BAY94-9172 的一步法放射性合成方便，可轻松应用于商业 PET 示踪剂合成器进行自动化合成。
