Abstract
BackgroundThe 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.AimTo 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.ResultsThe 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.
Highlights
Alzheimer’s disease (AD) is the leading cause of dementia in elderly people worldwide, which emerges as one of the significant challenges to the health care system in the twenty-first century [1].The typical pathophysiological changes of AD are the deposition of extracellular neuroinflammatory plaques1 3 Vol.:(0123456789)European Journal of Nuclear Medicine and Molecular Imaging and nerve fiber tangles in neurons
The present study aimed to evaluate the effectiveness of [18F]DRKXH1 in distinguishing AD patients from healthy individuals
The lipid-water distribution coefficient evaluated the lipophilicity of the probe and predicted the ability of the tracer to pass through the blood–brain barrier
Summary
Alzheimer’s disease (AD) is the leading cause of dementia in elderly people worldwide, which emerges as one of the significant challenges to the health care system in the twenty-first century [1].The typical pathophysiological changes of AD are the deposition of extracellular neuroinflammatory plaques1 3 Vol.:(0123456789)European Journal of Nuclear Medicine and Molecular Imaging and nerve fiber tangles in neurons. Advancing the diagnosis time of AD, in vivo imaging of Aβ plaques in the brain based on positron emission tomography (PET) plays an essential role in the pathophysiological mechanisms underlying AD development and the efficacy evaluation of the Aβ drug therapy [5]. The deposition of Aβ plaques in the brain of AD transgenic mice was determined by ex vivo autoradiography and immunohistochemistry. The small-animal PET study showed high initial brain uptake and rapid washout of [18F]DRKXH1. In vitro autoradiography showed a significant concentration of tracer in the Aβ plaque-rich areas in the brain of AD transgenic mice. 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
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