Structure–Activity Relationships of Radioiodinated 6,5,6-Tricyclic Compounds for the Development of Tau Imaging Probes

Abstract

Tau aggregate, which is the main component of the neurofibrillary tangle, is an attractive imaging target for diagnosing and monitoring the progression of Alzheimer's disease (AD). In this study, we designed and synthesized six radioiodinated 6,5,6-tricyclic compounds to explore novel scaffolds for tau imaging probes. On in vitro autoradiography of AD brain sections, pyridoimidazopyridine and benzimidazopyrimidine derivatives ([125I]21 and [125I]22, respectively) showed selective binding affinity for tau aggregates, whereas carbazole, pyrrolodipyridine, and pyridoimidazopyrimidine derivatives ([125I]10, [125I]12, and [125I]23, respectively) bound β-amyloid aggregates. In a biodistribution study using normal mice, [125I]21 and [125I]22 showed high initial uptakes (5.73 and 5.66% ID/g, respectively, at 2 min postinjection) into and rapid washout (0.14 and 0.10% ID/g, respectively, at 60 min postinjection) from the brain. Taken together, two novel scaffolds including pyridoimidazopyridine and benzimidazopyrimidine may be applied to develop useful tau imaging probes.