Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

Open Access 01-01-2022 | Alzheimer's Disease | Original Article

Preclinical and clinical study on [¹⁸F]DRKXH1: a novel β-amyloid PET tracer for Alzheimer’s disease

Authors: MiaoMiao Xu, Jun Guo, JiaCheng Gu, LinLin Zhang, ZiHao Liu, Lin Ding, HongLiang Fu, YuFei Ma, Sheng Liang, Hui Wang

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 2/2022

Abstract

Background

The deposition of β-amyloid (Aβ) in the brain is a biomarker of Alzheimer’s disease (AD). Highly sensitive Aβ positron emission tomography (PET) imaging plays an essential role in diagnosing and evaluating the therapeutic effects of AD.

Aim

To synthesize a new Aβ tracer [¹⁸F]DRKXH1 (5-(4-(6-(2-[18]fluoroethoxy)ethoxy)imidazo[1,2-alpha]pyridin-2-yl)phenyl) and evaluate the tracer performance by biodistribution analysis, in vivo small-animal PET-CT dynamic scan, ex vivo and in vitro autoradiography, and PET in human subjects.

Methods

[¹⁸F]DRKXH1 was synthesized automatically by the GE FN module. Log D (pH 7.4) and biodistribution of [¹⁸F]DRKXH1 were investigated. Small-animal-PET was used for [¹⁸F]DRKXH1 and [¹⁸F]AV45 imaging study in AD transgenic mice (APPswe/PSEN1dE9) and age-matched normal mice. The distribution volume ratios (DVR) and standardized uptake value ratios (SUVRs) were calculated with the cerebellum as the reference region. The deposition of Aβ plaques in the brain of AD transgenic mice was determined by ex vivo autoradiography and immunohistochemistry. In vitro autoradiography was performed in the postmortem brain sections of AD patients and healthy controls. Two healthy control subjects and one AD patient was subjected to in vivo PET study using [¹⁸F]DRKXH1.

Results

The yield of [¹⁸F]DRKXH1 was 40%, and the specific activity was 156.64 ± 11.55 GBq/μmol. [¹⁸F]DRKXH1 was mainly excreted through the liver and kidney. The small-animal PET study showed high initial brain uptake and rapid washout of [¹⁸F]DRKXH1. The concentration of [¹⁸F]DRKXH1 was detected in the cortex and hippocampus of AD transgenic mice brain. The cortex DVR of AD transgenic mice was higher than that of WT mice (P < 0.0001). Moreover, the SUVRs of AD transgenic mice were higher than those of WT mice based on the 0–60-min dynamic scanning. In vitro autoradiography showed a significant concentration of tracer in the Aβ plaque-rich areas in the brain of AD transgenic mice. The DVR value of [¹⁸F]-DRKXH1 is higher than that of [¹⁸F]-AV45 (1.29 ± 0.05 vs. 1.05 ± 0.08; t = 5.33, P = 0.0003). Autoradiography of postmortem human brain sections showed [¹⁸F]DRKXH1-labeled Aβ plaques in the AD brain. The AD patients had high retention in cortical regions, while healthy control subjects had uniformly low radioactivity uptake.

Conclusions

[¹⁸F]DRKXH1 is an Aβ tracer with high sensitivity in preclinical study and has the potential for in vivo detection of the human brain.

Available only for authorised users

Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet. 2016;388:505–17. https://doi.org/10.1016/s0140-6736(15)01124-1.CrossRefPubMed

2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016;12:459-509. https://doi.org/10.1016/j.jalz.2016.03.001.

Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179:312–39. https://doi.org/10.1016/j.cell.2019.09.001.CrossRefPubMedPubMedCentral

Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer’s disease: clinical trials and drug development. Lancet Neurol. 2010;9:702–16. https://doi.org/10.1016/s1474-4422(10)70119-8.CrossRefPubMed

Villemagne VL, Doré V, Burnham SC, Masters CL, Rowe CC. Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions. Nat Rev Neurol. 2018;14:225–36. https://doi.org/10.1038/nrneurol.2018.9.CrossRefPubMed

Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–19. https://doi.org/10.1002/ana.20009.CrossRefPubMed

Bacskai BJ, Hickey GA, Skoch J, Kajdasz ST, Wang Y, Huang GF, et al. Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A. 2003;100:12462–7. https://doi.org/10.1073/pnas.2034101100.CrossRefPubMedPubMedCentral

Johnson AE, Jeppsson F, Sandell J, Wensbo D, Neelissen JA, Juréus A, et al. AZD2184: a radioligand for sensitive detection of beta-amyloid deposits. J Neurochem. 2009;108:1177–86. https://doi.org/10.1111/j.1471-4159.2008.05861.x.CrossRefPubMed

Nelissen N, Van Laere K, Thurfjell L, Owenius R, Vandenbulcke M, Koole M, et al. Phase 1 study of the Pittsburgh compound B derivative 18F-flutemetamol in healthy volunteers and patients with probable Alzheimer disease. J Nucl Med. 2009;50:1251–9. https://doi.org/10.2967/jnumed.109.063305.CrossRefPubMed

10.

Choi SR, Golding G, Zhuang Z, Zhang W, Lim N, Hefti F, et al. Preclinical properties of 18F-AV-45: a PET agent for Abeta plaques in the brain. J Nucl Med. 2009;50:1887–94. https://doi.org/10.2967/jnumed.109.065284.CrossRefPubMed

11.

Newberg AB, Wintering NA, Plössl K, Hochold J, Stabin MG, Watson M, et al. Safety, biodistribution, and dosimetry of 123I-IMPY: a novel amyloid plaque-imaging agent for the diagnosis of Alzheimer’s disease. J Nucl Med. 2006;47:748–54.PubMed

12.

Cai L, Innis RB, Pike VW. Radioligand development for PET imaging of beta-amyloid (Abeta)–current status. Curr Med Chem. 2007;14:19–52. https://doi.org/10.2174/092986707779313471.CrossRefPubMed

13.

Chen CJ, Bando K, Ashino H, Taguchi K, Shiraishi H, Shima K, et al. Biological evaluation of the radioiodinated imidazo[1,2-a]pyridine derivative DRK092 for amyloid-β imaging in mouse model of Alzheimer’s disease. Neurosci Lett. 2014;581:103–8. https://doi.org/10.1016/j.neulet.2014.08.036.CrossRefPubMed

14.

Ma Y, Guo J, Liang S, Wang H. Improved automated synthesis of (2-((2–6-[18F]fluoro-5-(methylamino) pyridin-2-yl)benzothiazol-6-yl)thio)ethanol ([18F]FINH-Me) via direct radio-fluorination and quality control for Aβ-amyloid imaging. Q J Nucl Med Mol Imaging. 2019. https://doi.org/10.23736/s1824-4785.19.03163-7.CrossRefPubMed

15.

Liu Y, Zhu L, Plössl K, Choi SR, Qiao H, Sun X, et al. Optimization of automated radiosynthesis of [18F]AV-45: a new PET imaging agent for Alzheimer’s disease. Nucl Med Biol. 2010;37:917–25. https://doi.org/10.1016/j.nucmedbio.2010.05.001.CrossRefPubMedPubMedCentral

16.

Wang L, Cheng R, Fujinaga M, Yang J, Zhang Y, Hatori A, et al. A facile radiolabeling of [(18)F]FDPA via spirocyclic iodonium ylides: preliminary PET imaging studies in preclinical models of neuroinflammation. J Med Chem. 2017;60:5222–7. https://doi.org/10.1021/acs.jmedchem.7b00432.CrossRefPubMedPubMedCentral

17.

Tang D, Li J, Nickels ML, Huang G, Cohen AS, Manning HC. Preclinical evaluation of a novel TSPO PET ligand 2-(7-butyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N, N-diethylacetamide ((18)F-VUIIS1018A) to image glioma. Mol Imaging Biol. 2019;21:113–21. https://doi.org/10.1007/s11307-018-1198-7.CrossRefPubMedPubMedCentral

18.

Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996;16:834–40. https://doi.org/10.1097/00004647-199609000-00008.CrossRefPubMed

19.

Declercq L, Rombouts F, Koole M, Fierens K, Mariën J, Langlois X, et al. Preclinical evaluation of (18)F-JNJ64349311, a novel PET tracer for tau imaging. J Nucl Med. 2017;58:975–81. https://doi.org/10.2967/jnumed.116.185199.CrossRefPubMed

20.

Chen CJ, Bando K, Ashino H, Taguchi K, Shiraishi H, Shima K, et al. In vivo SPECT imaging of amyloid-β deposition with radioiodinated imidazo[1,2-a]pyridine derivative DRM106 in a mouse model of Alzheimer’s disease. J Nucl Med. 2015;56:120–6. https://doi.org/10.2967/jnumed.114.146944.CrossRefPubMed

21.

Guillozet AL, Smiley JF, Mash DC, Mesulam MM. Butyrylcholinesterase in the life cycle of amyloid plaques. Ann Neurol. 1997;42:909–18. https://doi.org/10.1002/ana.410420613.CrossRefPubMed

22.

Snellman A, López-Picón FR, Rokka J, Salmona M, Forloni G, Scheinin M, et al. Longitudinal amyloid imaging in mouse brain with 11C-PIB: comparison of APP23, Tg2576, and APPswe-PS1dE9 mouse models of Alzheimer disease. J Nucl Med. 2013;54:1434–41. https://doi.org/10.2967/jnumed.112.110163.CrossRefPubMed

23.

Toyama H, Ye D, Ichise M, Liow JS, Cai L, Jacobowitz D, et al. PET imaging of brain with the beta-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2005;32:593–600. https://doi.org/10.1007/s00259-005-1780-5.CrossRefPubMed

24.

Yamazaki Y, Kanekiyo T. Blood-brain barrier dysfunction and the pathogenesis of Alzheimer’s disease. Int J Mol Sci. 2017;18. https://doi.org/10.3390/ijms18091965.

25.

van de Haar HJ, Jansen JFA, van Osch MJP, van Buchem MA, Muller M, Wong SM, et al. Neurovascular unit impairment in early Alzheime’s disease measured with magnetic resonance imaging. Neurobiol Aging. 2016;45:190–6. https://doi.org/10.1016/j.neurobiolaging.2016.06.006.CrossRefPubMed

26.

Festoff BW, Sajja RK, van Dreden P, Cucullo L. HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease. J Neuroinflammation. 2016;13:194. https://doi.org/10.1186/s12974-016-0670-z.CrossRefPubMedPubMedCentral

27.

Rominger A, Brendel M, Burgold S, Keppler K, Baumann K, Xiong G, et al. Longitudinal assessment of cerebral β-amyloid deposition in mice overexpressing Swedish mutant β-amyloid precursor protein using 18F-florbetaben PET. J Nucl Med. 2013;54:1127–34. https://doi.org/10.2967/jnumed.112.114660.CrossRefPubMed

28.

Rominger A, Wagner E, Mille E, Böning G, Esmaeilzadeh M, Wängler B, et al. Endogenous competition against binding of [(18)F]DMFP and [(18)F]fallypride to dopamine D(2/3) receptors in brain of living mouse. Synapse. 2010;64:313–22. https://doi.org/10.1002/syn.20730.CrossRefPubMed

Title: Preclinical and clinical study on [18F]DRKXH1: a novel β-amyloid PET tracer for Alzheimer’s disease
Authors: MiaoMiao Xu
Jun Guo
JiaCheng Gu
LinLin Zhang
ZiHao Liu
Lin Ding
HongLiang Fu
YuFei Ma
Sheng Liang
Hui Wang
Publication date: 01-01-2022
Publisher: Springer Berlin Heidelberg
Keywords: Alzheimer's Disease
Positron Emission Tomography
Alzheimer's Disease
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 2/2022
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-021-05421-0

At a glance: The STEP trials

Springer Medicine

Preclinical and clinical study on [¹⁸F]DRKXH1: a novel β-amyloid PET tracer for Alzheimer’s disease

Abstract

Background

Aim

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Aim

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2022

[89Zr]Zr-huJ591 immuno-PET targeting PSMA in IDH mutant anaplastic oligodendroglioma

Image enhancement of whole-body oncology [18F]-FDG PET scans using deep neural networks to reduce noise

Coronavirus (COVID-19) pandemic mediated changing trends in nuclear medicine education and training: time to change and scintillate

EANM Springer Prizes 2021 awarded at EANM 2021

EANM procedure guidelines for brain PET imaging using [18F]FDG, version 3

Trimodality therapy for locally advanced esophageal squamous cell carcinoma: the role of volume-based PET/CT in patient management and prognostication