DOI QR코드

DOI QR Code

Optimized production method of [18F]flortaucipir injection for imaging tau pathology in patients with Alzheimer's disease

  • Kyung Rok Nam (Division of Applied RI, Korea Institute of Radiological & Medical Sciences) ;
  • Sang Jin Han (Division of Applied RI, Korea Institute of Radiological & Medical Sciences) ;
  • Nam Hun Lee (Division of Applied RI, Korea Institute of Radiological & Medical Sciences) ;
  • Min Yong Lee (Division of Applied RI, Korea Institute of Radiological & Medical Sciences) ;
  • Youngduk Kim (New Korea Industrial Co., LTD.) ;
  • Kyo Chul Lee (Division of Applied RI, Korea Institute of Radiological & Medical Sciences) ;
  • Yong Jin Lee (Division of Applied RI, Korea Institute of Radiological & Medical Sciences) ;
  • Young Hoon Ryu (Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Jae Yong Choi (Division of Applied RI, Korea Institute of Radiological & Medical Sciences)
  • Received : 2020.12.11
  • Accepted : 2020.12.29
  • Published : 2020.12.31

Abstract

Aggregated neurofibrillary tangles (NFTs) are a pathological hallmark in Alzheimer's disease (AD) and many radiopharmaceuticals targeting NFTs have been developed so far. Among these, [18F]flortaucipir (TAUVIDTM) is the first approved radiopharmaceutical in the Food and Drug Administration (FDA) to image tau pathology. In the present study, we describe the optimized radiosynthetic method for the routine production of [18F] flortaucipir using a commercialized automation module (i.e. GE TRACERlabTM FXFN pro). [18F]Flortaucipir was prepared by nucleophilic substitution from its N-tert-butoxycarbonyl protected nitro precursor, tertbutyl 7-(6-nitropyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate, at 130℃ for 10 min in dimethyl sulfoxide. The mean radiochemical yield was 20 ± 4.3% (decay-corrected, n = 47) with the molar activity of 218 ± 32 GBq/µmol at the end of synthesis. The radiochemical purity was determined to be above 95%. The overall production time including quality control is approximately 100min. The final produced [18F]flortaucipir injection meets the USP criteria for quality control. Thus, this fully automated system is validated for clinical use.

Keywords

Acknowledgement

This study was supported by a grant from the Korea Institute of Radiological and Medical Sciences (KIRAMS), by the Ministry of Science and ICT (MSIT), Republic of Korea (No. 50461-2020, 50536-2020)

References

  1. Braal J, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-59.
  2. https://www.cdc.gov/media/releases/2018/p0920-alzheimers-burden-double-2060.html
  3. https://www.nid.or.kr/info/today_list.aspx
  4. Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat. 1995;8:429-31.
  5. Ozudogru SN, Lippa CF. Disease modifying drugs targeting β-amyloid. Am J Alzheimers Dis Other Demen 2012;27:296-300.
  6. Serrano-Pozo A, Qian J, Muzikansky A, Monsell SE, Montine TJ, Frosch MP, Betensky RA, Hyman BT, Thal Amyloid Stages Do Not Significantly Impact the Correlation Between Neuropathological Change and Cognition in the Alzheimer Disease Continuum. J Neuropathol Exp Neurol 2016;75:516-526.
  7. Guillozet AL, Weintraub S, Mash DC, Mesulam MM, Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 2003;60:729-736.
  8. Leuzy A, Chiotis K, Lemoine L, Gillberg P-G, Almkvist O, Rodriquez-Vieitez E, Nordberg A. Tau PET imaging in neurodegenerative tauopathies-still a challenge. Mol Psychiatry 2019;24:1112-1134.
  9. Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su M-Y, Shankle WR, Elizarov A, Kolb HC, Early Clinical PET Imaging Results with the novel PHF-Tau Radioligand [F-18] T807. J Alzheimer's Disease 2013:457-468.
  10. Choi JY, Lyoo CH, Lee JH, Cho H, Kim KM, Kim JS, Ryu YH. Human Radiation Dosimetry of[18F]AV-1451(T807) to Detect Tau Pathology. Mol Imaging Biol 2016;18:479-482.
  11. Duyckaerts C, Brion JP, Hauw JJ, Flament-Durand J. Quantitative assessment of the density of neurofibrillary tangles and senile plaques in senile dementia of the Alzheimer type. Comparison of immunocytochemistry with a specific antibody and Bodian's protargol method. Acta Neuropathol 1987;73:167-170.
  12. Cho H, Choi JY, Hwang MS, Kim YJ, Lee HM, Lee HS, Lee JH, Ryu YH, Lee MS, Lyoo CH. In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann Neurol 2016;80:247-258.
  13. Marquie M, Normandin MD, Vanderburg CR, et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol 2015;78:787-800.
  14. https://www.fda.gov/drugs/new-drugs-fda-cdersnew-molecular-entities-and-new-therapeuticbiological-products/novel-drug-approvals-2020.
  15. Zhang W, Arteaga J, Cashion DK, Chen G, Gangadharmath U, Gomez LF, Kasi D, Lam C, Liang Q, Liu C, Mocharla VP, Mu F, Sinha A, Szardenings AK, Wang E, Walsh JC, Xia C, Yu C, Zhao T, Kolb HC. A highly selective and specific PET tracer for imaging of tau pathologies. J Alzheimers Dis 2012;31:601-12.
  16. Xia CF, Arteaga J, Chen G, Gangadharmath U, Gomez LF, Kasi D, Lam C, Liang Q, Liu C, Mocharla VP, Mu F, Sinha A, Su H, Szardenings AK, Walsh JC, Wang E, Yu C, Zhang W, Zhao T, Kolb HC. [18F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease. Alzheimers Demen 2013;9:666-76.
  17. Huang YY, Chiu MJ, Yen RF, Tsai CL, Hsieh HY, Chiu CH, Wu CH, Hsin LW, Tzen KY, Cheng CY, Ma KH, Shiue CY. An one-pot two-step automated synthesis of [18F]T807 injection, its biodistribution in mice and monkeys, and a preliminary study in humans. PLoS One 2019;7:e0217384.