4-(6-iodo-2-imidazo[1-2-a]pyridinyl)-N-N-dimethylaniline and Disease-Models--Animal

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, [(125)I]5 showed modest affinity for Aβ(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 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 [(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 Aβ 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.

Topics: Acridines; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Female; Iodine Radioisotopes; Mice; Mice, Inbred Strains; Mice, Transgenic; Molecular Structure; Myocardial Perfusion Imaging; Quinacrine

In a search for new probes to detect β-amyloid plaques in the brain of patients with Alzheimer's disease (AD), we have synthesized and evaluated a series of quinoxaline derivatives containing a '6+6-6' ring system. These quinoxaline derivatives showed excellent affinity for Aβ(1-42) aggregates with K(i) values ranging from 2.6 to 10.7nM. Autoradiography with sections of brain tissue from an animal model of AD mice (APP/PS1) and AD patients revealed that [(125)I]5 labeled β-amyloid plaques specifically. In biodistribution experiments using normal mice, [(125)I]5 displayed high uptake (6.03% ID/g at 2min) into and a moderately fast washout from the brain. Although additional refinements are needed to decrease the lipophilicity and improve the washout rate, the quinoxaline scaffold may be useful as a backbone structure to develop novel β-amyloid imaging agents.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autoradiography; Brain; Disease Models, Animal; Humans; Iodine Radioisotopes; Mice; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Protein Binding; Quinoxalines; Radiography; Radiopharmaceuticals; Tissue Distribution