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

ABSTRACT

The aim of the present study was to characterize the binding property of quinacrine-based acridine derivatives for Aß plaques and to evaluate this series of compounds as Aß imaging probes. Quinacrine clearly stained Aß plaques in the brain sections of Aß 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 Aß plaques in the brain slices of Tg2576 mice. In addition, [(125)I]5 showed modest affinity for Aß(1-42) aggregates with a K(d) value of 48 nM. Biodistribution studies using normal mice demonstrated that [(125)I]5 displayed poor initial brain uptake. Next, (125)I-labeled acridines without aliphatic amino groups were synthesized and characterized. Similar to quinacrine and 5, these compounds could detect Aß plaques in the brain sections of Tg2576 mice. It should be noted that the acridines showed much higher binding affinity for Aß aggregates and greater in vivo blood brain barrier permeability than [(125)I]5. Among them, 13 (6-Iodo-2-methoxy-9-methylaminoacridine) and 25 (2,9-Dimethoxy-6-iodo acridine) exhibited high affinity for the Aß aggregates with K(i) values of 14 and 29 nM, respectively. In the in vivo studies, [(125)I]13 and [(125)I]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.