Synthesis and biological evaluation of radioiodinated quinacrine-based derivatives for SPECT imaging of Aβ plaques

The aim of the present study was to characterize the binding property of quinacrine-based acridine derivatives for Aβ plaques and to evaluate this series of compounds as Aβ imaging probes. Quinacrine clearly stained Aβ plaques in the brain sections of Aβ deposition model transgenic mice (Tg2576 mice). Similarly, the quinacrine analog, 2-methoxy-9-(4-(dimethyl-1-methyl) -N-butyl) amino-6-iodo acridine (5), labeled Aβ plaques in the brain slices of Tg2576 mice. In addition, [125I]5 showed modest affinity for Aβ(1–42) aggregates with a Kd value of 48 nM. Biodistribution studies using normal mice demonstrated that [125I]5 displayed poor initial brain uptake. Next, 125I-labeled acridines without aliphatic amino groups were synthesized and characterized. Similar to quinacrine and 5, these compounds could detect Aβ plaques in the brain sections of Tg2576 mice. It should be noted that the acridines showed much higher binding affinity for Aβ aggregates and greater in vivo blood brain barrier permeability than [125I]5. Among them, 13 (6-Iodo-2-methoxy-9-methylaminoacridine) and 25 (2,9-Dimethoxy-6-iodo acridine) exhibited high affinity for the Aβ aggregates with Ki values of 14 and 29 nM, respectively. In the in vivo studies, [125I]13 and [125I]25 showed excellent initial brain uptake (3.0 and 4.4% dose/g, respectively, at 2 min) with fast washout from the brain (0.33 and 0.37% dose/g, respectively, at 60 min). These acridine derivatives are demonstrated to be promising SPECT imaging probes for amyloid in the living brain. [Display omitted] ► Radioiodinated quinacrine-based derivatives have been developed as novel amyloid imaging probes. ► Removal of aliphatic amino groups of quinacrine increased binding affinity for Aβ(1–42) aggregates. ► Compounds 13 and 25 exhibited high binding affinity for Aβ(1–42) aggregates. ► [125I]13 and [125I]25 showed excellent initial brain uptake with fast washout from the brain under in vivo condition.