PHF-Tau蛋白正子造影劑[F-18] T807之GMP自動化生產與其在正常小鼠體內的全身造影

GMP-Compliant Radiosynthesis of [F-18] T807 and Its Whole-Body Biodistribution via Whole-Body PET Imaging of Mice

邱晉宏(Ching-Hung Chiu) ； 黃雅瑤(Ya-Yao Huang) ； 蔡佳伶(Chia-Ling Tsai) ； 謝浩宇(Hao-Yu Hsieh) ； 忻凌偉(Ling-Wei Hsin) ； 曾凱元(Kai-Yuan Tzen) ； 顏若芳(Ruoh-Fang Yen) ； 薛晴彥(Chyng-Yann Shiue)

《核子醫學暨分子影像雜誌》 31卷3期 (2018/09) Pp. 136-145

https://doi.org/10.6332/ANMMI.201809_31(3).0003

摘要

背景：研究阿茲海默氏症的病人之paired helical filament-tau (PHF-tau)蛋白病正子造影，[F-18] T807已經被證實極具潛力的正子藥物。為了將此藥物順利地應用於人體試驗研究，本中心改良了合成方式，並嘗試在人體試驗研究計畫執行前先以正常小鼠觀察[F-18] T807在小鼠之生物學分布。方法：藉由改良文獻報導之合成方式，以GE TRACERlab FX_(FN)合成器進行[F-18] T807自動化生產。再將約7.4 MBq的注入雄性institute of cancer research (ICR)小鼠(n = 4)並進行小鼠動態造影以瞭解小鼠全身的生物分布。結果：成功地自動化生產出[F-18] T807，且放射化學產率約13 ± 4% (end of synthesis [EOS] n ＞ 3)合成時間大約70分鐘。產品化學及放射化學純度皆大於95%，且藥物之比活度為152 ± 52 GBq/μmol。動物造影結果顯示，大部分[F-18] T807的活度位於膽囊及大腸末端，且會隨著時間而增加。結論：由本研究得知此改良方法不僅可以穩定地生產高品質之[F-18] T807注射液以供臨床病人使用，甚至其臨床前動物造影結果亦可佐證本院製造的[F-18] T807注射液在活體使用的藥動學與安全性。目前，因應本院臨床試驗，以上[F-18] T807合成方法與品管規格也已經彙整成Taiwan Food and Drug Administration (TFDA)臨床試驗審查(investigational new drug, IND)審查之必要文件：化學製造管制(Chemistry, Manufacturing and Controls, CMC)。因此，本研究結果對於未來其他臺灣醫院之臨床藥物生產與後續的IND審查，相信有一定的實際應用價值。

關鍵字

[F-18] T807 ； PHF-tau蛋白 ； 阿茲海默氏症 ； GMP ； microPET

並列摘要

Background: [F-18] T807 has been proved to be a promising paired helical filament-tau (PHF-tau) tracer for studying Alzheimer's disease (AD) in humans. However, the reported methods for [F-18] T807 production were somewhat complicated. In order to use this tracer for human studies, we improved its synthesis and studied its whole-body biodistribution in mice before human studies were undertaken. Methods: The [F-18] T807 was synthesized in a GE TRACERlab-FX_(FN) module as reported previously with some modifications. For animal study, fasten male institute of cancer research (ICR) mice (n = 4) was injected with a bolus of about 7.4 MBq of [F-18] T807. Results: The radiochemical yield of [F-18] T807 synthesized by this method was 13 ± 4% (end of synthesis [EOS] n ＞ 3) in a synthesis time of ~ 70 min. Both the chemical and radiochemical purity were ＞ 95% with a specific activity of 152 ± 52 GBq/μmol. Whole-body biodistribution in mice showed that the radioactivity in the gallbladder and lower large intestine increased with time. Conclusions: Automated production of [F-18] T807 has been successfully achieved with high reliability at National Taiwan University Hospital. Moreover, it would be applied to clinical supply of [F-18] T807 injection with high quality. Furthermore, our preclinical results could be supportive evidences for safety and pharmakinetics of [F-18] T807. Now, all synthetic and quality data of [F- 18] T807 have been further organized to the requisite document for Taiwan Food and Drug Administration (TFDA) investigational new drug (IND) submission, i.e., Chemistry, Manufacturing and Controls (CMC). All results for this study will be useful information for clinical production and TFDA IND submission in other hospitals of Taiwan.

並列關鍵字

[F-18] T807 ； PHF-tau ； Alzheimer's disease ； GMP ； microPET