RESUMEN
High-resolution scans of immunohistochemical (IHC) stains of Alzheimer's disease (AD) brain slices and radioligand autoradiography both provide information about the distribution of Aß plaques and Tau, the two common proteinopathies in AD. Accurate assessment of the amount and regional location of Aß plaques and Tau is essential to understand the progression of AD pathology. Our goal was to develop a quantitative method for the analysis of IHC-autoradiography images. Postmortem anterior cingulate (AC) and corpus callosum (CC) from AD and control (CN) subjects were IHC stained with anti-Aß for Aß plaques and autoradiography with [18F]flotaza and [125I]IBETA for Aß plaques. For Tau, [124I]IPPI, a new radiotracer, was synthesized and evaluated in the AD brain. For Tau imaging, brain slices were IHC stained with anti-Tau and autoradiography using [125I]IPPI and [124I]IPPI. Annotations for Aß plaques and Tau using QuPath for training and pixel classifiers were generated to measure the percent of the area of Aß plaques and Tau in each slice. The binding of [124I]IPPI was observed in all AD brains with an AC/CC ratio > 10. Selectivity to Tau was shown by blocking [124I]IPPI with MK-6240. Percent positivity for Aß plaques was 4-15%, and for Tau, it was 1.3 to 35%. All IHC Aß plaque-positive subjects showed [18F]flotaza and [125I]IBETA binding with a positive linear correlation (r2 > 0.45). Tau-positive subjects showed [124/125I]IPPI binding with a stronger positive linear correlation (r2 > 0.80). This quantitative IHC-autoradiography approach provides an accurate measurement of Aß plaques and Tau within and across subjects.
RESUMEN
Several fluorine-18-labeled PET ß-amyloid (Aß) plaque radiotracers for Alzheimer's disease (AD) are in clinical use. However, no radioiodinated imaging agent for Aß 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 Aß 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 Aß plaques. We report our findings on the radioiododestannylation reaction used to prepare [124/125I]IBETA and evaluate its binding to Aß 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 Aß plaques was high in the frontal cortex, anterior cingulate, thalamus, and hippocampus, which are regions of high Aß 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 Aß plaques compared to white matter (ratio of gray to white matter was >5). Anti-Aß 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 Aß 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 Aß plaques. Some deiodination was observed at later time points. Therefore, [124I]IBETA may potentially be a useful PET radioligand for Aß plaques in brain studies.