Preclinical Properties of ¹⁸F-AV-45: A PET Agent for Aβ Plaques in the Brain

Abstract

β-amyloid plaques (Aβ plaques) in the brain, containing predominantly fibrillary Aβ peptide aggregates, represent a defining pathologic feature of Alzheimer disease (AD). Imaging agents targeting the Aβ plaques in the living human brain are potentially valuable as biomarkers of pathogenesis processes in AD. (E)-4-(2-(6-(2-(2-(2-¹⁸F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine (¹⁸F-AV-45) is such as an agent currently in phase III clinical studies for PET of Aβ plaques in the brain. Methods: In vitro binding of ¹⁸F-AV-45 to Aβ plaques in the postmortem AD brain tissue was evaluated by in vitro binding assay and autoradiography. In vivo biodistribution of ¹⁸F-AV-45 in mice and ex vivo autoradiography of AD transgenic mice (APPswe/PSEN1) with Aβ aggregates in the brain were performed. Small-animal PET of a monkey brain after an intravenous injection of ¹⁸F-AV-45 was evaluated. Results: ¹⁸F-AV-45 displayed a high binding affinity and specificity to Aβ plaques (K_d, 3.72 ± 0.30 nM). In vitro autoradiography of postmortem human brain sections showed substantial plaque labeling in AD brains and not in the control brains. Initial high brain uptake and rapid washout from the brain of healthy mice and monkey were observed. Metabolites produced in the blood of healthy mice after an intravenous injection were identified. ¹⁸F-AV-45 displayed excellent binding affinity to Aβ plaques in the AD brain by ex vivo autoradiography in transgenic AD model mice. The results lend support that ¹⁸F-AV-45 may be a useful PET agent for detecting Aβ plaques in the living human brain.