Biphenyls labeled with technetium 99m for imaging β-amyloid plaques in the brain

Formation and accumulation of excess aggregates of beta-amyloid (A) plaques in the brain are critical factors contributing to the development and progression of Alzheimer's disease (AD). There is an urgent need for in vivo imaging agents that can specifically demonstrate the location and density of A plaques in the brain. The aim of this study was to develop potential technetium 99m (Tc-99m)labeled diagnostic imaging agents specific for the detection of A beta plaques. Based on previously obtained A plaque-specific biphenyls containing a p-N, N-dimethylaminophenyl group, a series of Tc-99m and RC-N2S2-biphenyl derivatives was prepared. The stable neutral and lipophilic Te-99m complexes, [Tc-99m]19 and [Tc-99m]23, A+B, were successfully obtained. As surrogates for the Tc-99m complexes, the corresponding surrogates, Re complexes of 23, were also prepared. Surprisingly, it was found that the Re complexes showed distinctively different retention profiles as compared with the corresponding Tc-99m complexes. Biodistribution studies indicated that [Tc-99m]23A readily passed through the blood-brain barrier (1.18% dose/brain at 2 min) in contrast to the low brain penetration of [Tc-99m]19 (0.29% dose/brain at 2 min). Initial results suggested that [Tc-99m]23A showed selective binding to the A beta plaque-like structures in the brain sections from transgenic mice but not in the postmortem human brain tissue of patients with confirmed AD. The results provide encouraging evidence that development of a Tc-99m-labeled agent for imaging A beta plaques in the brain may be feasible. Caution should be taken when comparing these Tc-99m complexes with the corresponding surrogates - the Re complexes. (c) 2005 Elsevier Inc. All rights reserved.