[124I]IBETA: A New Aβ Plaque Positron Emission Tomography Imaging Agent for Alzheimer’s Disease

Abstract

Several fluorine-18-labeled PET β-amyloid (Aβ) plaque radiotracers for Alzheimer’s disease (AD) are in clinical use. However, no radioiodinated imaging agent for Aβ plaques has been successfully moved forward for either single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Radioiodinated pyridyl benzofuran derivatives for the SPECT imaging of Aβ plaques using iodine-123 and iodine-125 are being pursued. In this study, we assess the iodine-124 radioiodinated pyridyl benzofuran derivative 5-(5-[124I]iodobenzofuran-2-yl)-N,N-dimethylpyridin-2-amine ([124I]IBETA) (Ki = 2.36 nM) for utilization in PET imaging for Aβ plaques. We report our findings on the radioiododestannylation reaction used to prepare [124/125I]IBETA and evaluate its binding to Aβ plaques in a 5 × FAD mouse model and postmortem human AD brain. Both [125I]IBETA and [124I]IBETA are produced in >25% radiochemical yield and >85% radiochemical purity. The in vitro binding of [125I]IBETA and [124I]IBETA in transgenic 5 × FAD mouse model for Aβ plaques was high in the frontal cortex, anterior cingulate, thalamus, and hippocampus, which are regions of high Aβ accumulation, with very little binding in the cerebellum (ratio of brain regions to cerebellum was >5). The in vitro binding of [125I]IBETA and [124I]IBETA in postmortem human AD brains was higher in gray matter containing Aβ plaques compared to white matter (ratio of gray to white matter was >5). Anti-Aβ immunostaining strongly correlated with [124/125I]IBETA regional binding in both the 5 × FAD mouse and postmortem AD human brains. The binding of [124/125I]IBETA in 5 × FAD mouse and postmortem human AD brains was displaced by the known Aβ plaque imaging agent, Flotaza. Preliminary PET/CT studies of [124I]IBETA in the 5 × FAD mouse model suggested [124I]IBETA was relatively stable in vivo with a greater localization of [124I]IBETA in the brain regions with a high concentration of Aβ plaques. Some deiodination was observed at later time points. Therefore, [124I]IBETA may potentially be a useful PET radioligand for Aβ plaques in brain studies.

Abnormal [18F]NIFENE binding in transgenic 5xFAD mouse model of Alzheimer's disease: In vivo PET/CT imaging studies of α4β2* nicotinic acetylcholinergic receptors and in vitro correlations with Aβ plaques

“…Our recent findings using brain slices in vitro autoradiography and in vivo PET confirmed Aβ plaque accumulation in 5xFAD mice using the imaging agent [ 124/125 I]IBETA (Nguyen et al., 2022). Human AD brain slices were also successfully labeled with [ 124/125 I]IBETA suggesting similarity of binding sites in the 5xFAD mice and human Aβ plaques (Nguyen et al., 2022). Thus, 5xFAD mice would be a good transgenic mouse model to study the effects of Aβ plaques on α4β2* nAChR.…”

“…The 5xFAD mice expressing Aβ plaques were found to be an excellent model to examine potential alterations in α4β2* nAChRs. The presence of Aβ plaques in these mice were confirmed in these mice using [ 124/125 I]IBETA and anti-Aβ IHC (Nguyen et al, 2022) and [ 18 F]flotaza (Kaur et al, 2021) and were consistent with the findings of [ 18 F]florbetaben (Boulter et al, 2021). In vitro binding of [ 125 I]IBETA and [ 124 I]IBETA in transgenic 5xFAD mouse model for Aβ plaques was high in the frontal cortex, anterior cingulate, thalamus, and hippocampus, which were regions of high Aβ accumulation, with very little binding in the cerebellum (ratio of brain regions to cerebellum was >5).…”

“…PET imaging studies in the 5xFAD transgenic mice have been carried out using various PET probes including Aβ plaque imaging [ 18 F]florbetaben (Boulter et al, 2021;Jullienne et al, 2022). Our recent findings using brain slices in vitro autoradiography and in vivo PET confirmed Aβ plaque accumulation in 5xFAD mice using the imaging agent [ 124/125 I]IBETA (Nguyen et al, 2022). Human AD brain slices were also successfully labeled with [ 124/125 I]IBETA suggesting similarity of binding sites in the 5xFAD mice and human Aβ plaques (Nguyen et al, 2022).…”

“…Nonspecific binding was measured in the presence of flotaza (Kaur et al, 2021). The slices were then washed with cold PBS buffer, 90% ethanolic PBS buffer twice, PBS buffer, and cold water (Nguyen et al, 2022). The brain sections were air dried, exposed overnight on a phosphor film, and then read on the Cyclone Storage Phosphor System.…”

“…Regional brain distribution of high Aβ plaque accumulation, determined using fluorescence imaging and anti‐Aβ immunohistochemistry have been reported (Forner et al., 2021; Oblak et al., 2021). Radioligand autoradiography in the 5xFAD brains confirms Aβ plaques in cortex, including anterior cingulate, frontal cortex, hippocampus, lateral septal nuclei, and thalamic brain regions (Nguyen et al., 2022). Normal mouse brain distribution of [ 18 F]nifene binding includes cortex, including anterior cingulate, frontal cortex, thalamus, subiculum (with low levels in the hippocampus, mostly in the dentate gyrus), and striatum with very low levels in the cerebellum (Campoy et al., 2021) Thus, there are several overlapping mouse brain regions where Aβ plaques and α4β2* nAChRs are localized.…”