Synthesis and biological evaluation of radioiodinated quinacrinebased derivatives for SPECT imaging of A plaques

The aim of the present study was to characterize the binding property of quinacrine-based acridine derivatives for A plaques and to evaluate this series of compounds as A imaging probes. Quinacrine clearly stained A plaques in the brain sections of A 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 A plaques in the brain slices of Tg2576 mice. In addition, [125I]5 showed modest affinity for A(1e42) 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 A plaques in the brain sections of Tg2576 mice. It should be noted that the acridines showed much higher binding affinity for A 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 A 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.