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PET Radioligands for Imaging of Tau Pathology: Current Status

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Abstract

The incidence of Alzheimer’s disease (AD), a progressive neurodegenerative disorder, continues to soar with the rapid growth of the elderly population, thus creating an enormous social and economic burden. Although disease-modifying drugs to treat AD are not yet available, several candidate drugs are in clinical trials. Most of these drugs are expected to be effective at the early stages of the disease, and therefore the early and accurate diagnosis of AD will be a critical factor in efforts to improve the prognosis of patients with AD. This review focuses on lead radioligands developed to date and their preclinical data in order to facilitate the development of tau-specific positron emission tomography radioligands that are of great interest to the scientific community.

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References

  1. Bartus RT, Dean RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982;217:408–14.

    Article  CAS  PubMed  Google Scholar 

  2. Davies P, Maloney AJF. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet. 1976;2:1403.

    Article  CAS  PubMed  Google Scholar 

  3. Bowen DM, Benton JS, Spillane JA, Smith CC, Allen SJ. Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. J Neurol Sci. 1982;57:191–202.

    Article  CAS  PubMed  Google Scholar 

  4. Geula C, Mesulam MM. Cholinergic systems and related neuropathological predilection patterns in Alzheimer disease. In: Terry RD, Katzman R, Back KL, editors. Alzheimer disease. New York: Raven; 1994. p. 263–91.

    Google Scholar 

  5. Davis KL, Mohs RC, Marin D, Purohit DP, Perl DP, Lantz M, et al. Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA. 1999;281:1401–6.

    Article  CAS  PubMed  Google Scholar 

  6. Doody RS, Dunn JK, Clark CM, Farlow M, Foster NL, Liao T, et al. Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2001;12:295–300.

    Article  CAS  PubMed  Google Scholar 

  7. Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, et al. AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet. 2004;363:2105–15.

    Article  CAS  PubMed  Google Scholar 

  8. Craig LA, Hong NS, McDonald RJ. Revisiting the cholinergic hypothesis in the development of Alzheimer’s disease. Neurosci Biobehav Rev. 2011;35:1397–409.

    Article  CAS  PubMed  Google Scholar 

  9. Irie T, Fukushi K, Akimoto Y, Tamagami H, Nozaki T. Design and evaluation of radioactive acetylcholine analog for mapping brain acetylcholinesterase (AChE) in vivo. Nucl Med Biol. 1994;21:801–8.

    Article  CAS  PubMed  Google Scholar 

  10. Kilbourn MR, Snyder SE, Sherman PS, Kuhl DE. In vivo studies of acetylcholinesterase activity using a labeled substrate, N-[11C]methylpiperidin-4-yl propionate ([11C]PMP). Synapse. 1996;22:123–31.

    Article  CAS  PubMed  Google Scholar 

  11. Namba H, Irie T, Fukushi K, Iyo M. In vivo measurement of acetylcholinesterase activity in the brain with a radioactive acetylcholine analog. Brain Res. 1994;667:278–82.

    Article  CAS  PubMed  Google Scholar 

  12. Musachio JL, Flesher JE, Scheffel U, Rauseo P, Hilton J, Mathews WB, et al. Radiosynthesis and mouse brain distribution studies of [11C] CP-126,998: a PET ligand for in vivo study of acetylcholinesterase. Nucl Med Biol. 2002;29:547–52.

    Article  CAS  PubMed  Google Scholar 

  13. Bencherif B, Endres CJ, Musachio JL, Villalobos A, Hilton J, Scheffel U, et al. PET imaging of brain acetylcholinesterase using [11C]CP-126,998, a brain selective enzyme inhibitor. Synapse. 2002;45:1–9.

    Article  CAS  PubMed  Google Scholar 

  14. Lee SY, Choe YS, Kim YR, Paik JY, Choi BW, Kim SE, et al. Synthesis and evaluation of 5,7-dihydro-3-(2-(1-(4-[18F]fluorobenzyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2-f)-1,2-benzisoxazol-6-one for in vivo mapping of acetylcholinesterase. Nucl Med Commun. 2004;25:591–6.

    Article  CAS  PubMed  Google Scholar 

  15. Ryu EK, Choe YS, Park EY, Paik JY, Kim YR, Lee KH, et al. Synthesis and evaluation of 2-[18F]fluoro-CP-118,954 for the in vivo mapping of acetylcholinesterase. Nucl Med Biol. 2005;32:185–91.

    Article  CAS  PubMed  Google Scholar 

  16. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10:698–712.

    Article  CAS  PubMed  Google Scholar 

  17. Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem. 2003;46:2740–54.

    Article  CAS  PubMed  Google Scholar 

  18. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging β-amyloid burden in aging and dementia. Neurology. 2007;68:1718–25.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang W, Kung MP, Oya S, Hou C’, Kung HF. 18F-Labeld styrylpyridines as PET agents for amyloid plaque imaging. Nucl Med Biol. 2007;34:89–97.

    Article  CAS  PubMed  Google Scholar 

  20. Kung HF, Choi SR, Qu W, Zhang W, Skovronsky D. 18F Stilbenes and styrylpyridines for PET imaging of Aβ plaques in Alzheimer’s disease: a miniperspective. J Med Chem. 2010;53:933–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Clark CM, Schneider JA, Mintun MA, Bedell BJ, Beach TG, Sadowsky CH, et al. Phase III trial results for the amyoid PET imaging agent Florbetapir F 18 (18F-AV-45): imaging to histopathologic correlations in an end-of-life human subject study. Alzheimers Dement. 2010;6:S71.

    Article  Google Scholar 

  22. Zhang W, Kung MP, Hou C, Marier DL, Kung HF. F-18 Polyethylene glycol stilbenes as PET imaging agents targeting Aβ aggregates in the brain. Nucl Med Biol. 2005;32:799–809.

    Article  CAS  PubMed  Google Scholar 

  23. Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O’Keefe G, et al. Imaging of amyloid β in Alzheimer’s disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol. 2008;7:129–35.

    Article  CAS  PubMed  Google Scholar 

  24. Sabri O, Sabbagh MN, Seibyl J, Barthel H, Akatsu H, Ouchi Y, et al. Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer disease: phase 3 study. Alzheimers Dement. 2015;11:964–74.

    Article  PubMed  Google Scholar 

  25. Koole M, Lewis DM, Buckley C, Nelissen N, Vandenbulcke M, Brooks DJ, et al. Whole-body biodistribution and radiation dosimetry of 18F-GE067: a radioligand for in vivo brain amyloid imaging. J Nucl Med. 2009;50:818–22.

    Article  CAS  PubMed  Google Scholar 

  26. Curtis C, Gamez JE, Singh U, Sadowsky H, Villena T, Sabbagh MN, et al. Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density. JAMA Neurol. 2015;72:287–94.

    Article  PubMed  Google Scholar 

  27. Ghoshal N, García-Sierra F, Wuu J, Leurgans S, Bennett DA, et al. Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimer’s disease. Exp Neurol. 2002;177:475–93.

    Article  CAS  PubMed  Google Scholar 

  28. Shah M, Catafau AM. Molecular imaging insights into neurodegeneration: focus on tau PET radiotracers. J Nucl Med. 2014;55:871–4.

    Article  CAS  PubMed  Google Scholar 

  29. Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC. Tau imaging: early progress and future directions. Lancet Neurol. 2015;14:114–24.

    Article  PubMed  Google Scholar 

  30. Ittner LM, Götz J. Amyloid-β and tau — a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci. 2011;12:67–72.

    Article  Google Scholar 

  31. Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 1992;8:159–68.

    Article  CAS  PubMed  Google Scholar 

  32. Lee VMY, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121–59.

    Article  CAS  PubMed  Google Scholar 

  33. Chen-Plotkin AS, Lee VMY, Trojanowski JQ. TAR DNA-binding protein 43 in neurodegenerative disease. Nat Rev Neurol. 2010;6:211–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Rabinovici GD, Miller BL. Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs. 2010;24:375–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry. 2011;82:476–86.

    Article  PubMed  Google Scholar 

  36. Sunde M, Serpell LC, Bartlam M, Fraser PE, Pepys MB, Blake CC. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J Mol Biol. 1997;273:729–39.

    Article  CAS  PubMed  Google Scholar 

  37. Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, et al. 3D structure of Alzheimer’s amyloid-β(1–42) fibrils. Proc Natl Acad Sci U S A. 2005;102:17342–7.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Scheidt HA, Huster D, Rothemund I, Morgado S. Dynamics of amyloid fibrils revealed by solid-state NMR. J Biol Chem. 2012;287:2017–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Daebel V, Chinnathambi S, Biernat J, Schwalbe M, Habenstein B, Loquet A, et al. β-Sheet core of tau paired helical filaments revealed by solid-state NMR. J Am Chem Soc. 2012;134:13982–9.

    Article  CAS  PubMed  Google Scholar 

  40. Okamura N, Furumoto S, Harada R, Tago T, Yoshikawa T, Fodero-Tavoletti M, et al. Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J Nucl Med. 2013;54:1420–7.

    Article  CAS  PubMed  Google Scholar 

  41. Mukaetova-Ladinska EB, Harrington CR, Roth M, Wischik CM. Biochemical and anatomical redistribution of tau protein in Alzheimer’s disease. Am J Pathol. 1993;143:565–78.

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Näslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000;283:1571–7.

    Article  PubMed  Google Scholar 

  43. Mathis CA, Klunk WE. Imaging tau deposits in vivo: progress in viewing more of the proteopathy picture. Neuron. 2013;79:1035–7.

    Article  CAS  PubMed  Google Scholar 

  44. Barrio JR, Huang SC, Cole G, Satyamurthy N, Petric A, Phelps ME, et al. PET imaging of tangles and plaques in Alzheimer disease with a highly hydrophobic probe. J Label Compd Radiopharm. 1999;42:S194–5.

    Google Scholar 

  45. Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthaylethylidene derivatives as positron emission tomography imaging probes of β-amyloid plaques in Alzheimer’s disease. J Neurosci. 2001;21:RC189.

    CAS  PubMed  Google Scholar 

  46. Harada R, Okamura N, Furumoto S, Tago T, Maruyama M, Higuchi M, et al. Comparison of the binding characteristics of [18F]THK-523 and other amyloid imaging tracers to Alzheimer’s disease pathology. Eur J Nucl Med Mol Imaging. 2013;40:125–32.

    Article  CAS  PubMed  Google Scholar 

  47. Okamura N, Suemoto T, Furumoto S, Suzuki M, Shimadzu H, Akatsu H, et al. Quinoline and benzimidazole derivatives: candidate probes for in vivo imaging of tau pathology in Alzheimer’s disease. J Neurosci. 2005;25:10857–62.

    Article  CAS  PubMed  Google Scholar 

  48. Rojo LE, Alzate-Morales J, Saavedra IN, Davies P, Maccioni RB. Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer’s disease. J Alzheimers Dis. 2010;19:573–89.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Riss PJ, Brichard L, Ferrari V, Williamson DJ, Fryer TD, Hong YT, et al. Radiosynthesis and characterization of astemizole derivatives as lead compounds toward PET imaging of τ-pathology. Med Chem Commun. 2013;4:852–5.

    Article  CAS  Google Scholar 

  50. Shao X, Carpenter GM, Desmond TJ, Sherman P, Quesada CA, Maria Fawaz M, et al. Evaluation of [11C]N-methyl lansoprazole as a radiopharmaceutical for PET imaging of tau neurofibrillary tangles. ACS Med Chem Lett. 2012;3:936–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Fawaz MV, Brooks AF, Rodnick ME, Carpenter GM, Shao X, Desmond TJ, et al. High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer’s disease and progressive supranuclear palsy: Synthesis, preclinical evaluation, and lead selection. ACS Chem Neurosci. 2014;5:718–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Harada R, Okamura N, Furumoto S, Furukawa K, Ishiki A, Tomita N, et al. [18F]THK-5117 PET for assessing neurofibrillary pathology in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2015;42:1052–61.

    Article  CAS  PubMed  Google Scholar 

  53. Okamura N, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Harada R, Yates P, et al. Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET. Brain. 2014;137:1762–71.

    Article  PubMed  Google Scholar 

  54. Okamura N, Furumoto S, Harada R, Tago T, Iwata R, Tashiro M, et al. Characterization of 18F-THK-5351, a novel PET tracer for imaging tau pathology in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2014;41 Suppl 2:260.

    Google Scholar 

  55. Okamura N, Furumoto S, Furukawa K, Ishiki A, Harada R, Iwata R, et al. PET imaging of tau pathology in mild cognitive impairment and Alzheimer’s disease with [18F]THK-5351. J Nucl Med. 2015;56 Suppl 3:138.

    Google Scholar 

  56. Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013;79:1094–108.

    Article  CAS  PubMed  Google Scholar 

  57. Hashimoto H, Kawamura K, Igarashi N, Takei M, Fujishiro T, Aihara Y, et al. Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of tau pathology. J Nucl Med. 2014;55:1–7.

    Article  Google Scholar 

  58. Zhang W, Arteaga J, Cashion DK, Chen G, Gangadharmath U, Gomez LF, et al. A highly selective and specific PET tracer for imaging of tau pathologies. J Alzheimers Dis. 2012;31:601–12.

    CAS  PubMed  Google Scholar 

  59. Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su MY, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis. 2013;34:457–68.

    CAS  PubMed  Google Scholar 

  60. Shoup TM, Yokell DL, Rice PA, Jackson RN, Livni E, Johnson KA, et al. A concise radiosynthesis of the tau radiopharmaceutical, [18F]T807. J Label Compd Radiopharm. 2013;56:736–40.

    Article  CAS  Google Scholar 

  61. Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su MY, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T808. J Alzheimers Dis. 2014;38:171–84.

    PubMed  Google Scholar 

  62. Xia CF, Arteaga J, Chen G, Gangadharmath U, Gomez LF, Kasi D, et al. [18F]T807, a novel tau positron emission tomography imaging agent for Alzheimer’s disease. Alzheimers Dement. 2013;9:666–76.

    Article  PubMed  Google Scholar 

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Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant (NRF-2011-0030164) and the Basic Science Research Program through the NRF (#2012R1A1A2041354) funded by the Korean government (MEST).

Conflict of Interest

Yearn Seong Choe and Kyung-Han Lee declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea

    Yearn Seong Choe & Kyung-Han Lee

  2. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Korea

    Yearn Seong Choe & Kyung-Han Lee

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  1. Yearn Seong Choe
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  2. Kyung-Han Lee
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Correspondence to Kyung-Han Lee.

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The study was approved by an institutional review board or equivalent and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. This article does not contain any studies with humans or animals performed by any of the authors.

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Choe, Y.S., Lee, KH. PET Radioligands for Imaging of Tau Pathology: Current Status. Nucl Med Mol Imaging 49, 251–257 (2015). https://doi.org/10.1007/s13139-015-0374-9

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