In Vivo SPECT Imaging of Amyloid-beta Deposition with Radioiodinated Imidazo[1,2-a] Pyridine Derivative DRM106 in a Mouse Model of Alzheimer's Disease

摘要

Noninvasive determination of amyloid-beta peptide (A beta) deposition has important significance for early diagnosis and medical intervention for Alzheimer's disease (AD). In the present study, we investigated the availability of radiolabeled DRM106 (I-123/125-DRM106 [6-iodo-2[ 4-(1H-3-pyrazolyl) phenyl] imidazo[1,2-a] pyridine]), a compound with sufficient affinity for the synthesis of human A beta fibrils and satisfactory metabolic stability, as a SPECT ligand in living brains. Method: The sensitivity of I-125-DRM106 for detecting A beta deposition was compared with that of I-125-IMPY (2-(4'-dimethylaminophenyl)-6-iodo-imidazo[1,2-a] pyridine), a well-known amyloid SPECT ligand, by ex vivo autoradiographic analyses in 18-mo-old amyloid precursor protein transgenic mice. To verify the sensitivity and quantitation of radiolabeled DRM106 for in vivo imaging, we compared the detectability of A beta plaques with I-123-DRM106 and a well-known amyloid PET agent, C-11-labeled Pittsburgh compound B (C-11-PiB), in 29-mo-old transgenic mice and age-matched nontransgenic littermates. Additionally, we compared the binding characteristics of I-125-DRM106 with those of C-11-PiB and C-11-PBB3, which selectively bind to A beta plaques and preferentially to tau aggregates, respectively, in postmortem AD brain sections. Results: Ex vivo autoradiographic analysis showed that measurement with I-125-DRM106 has a higher sensitivity for detecting A beta accumulation than with I-125-IMPY in transgenic mice. SPECT imaging with I-123-DRM106 also successfully detected A beta deposition in living aged transgenic mice and showed strong correlation (R = 0.95, P < 0.01) in quantitative analysis for A beta plaque detection by PET imaging with C-11-PiB, implying that sensitivity and quantitation of SPECT imaging with I-123-DRM106 are almost as good as C-11-PiB PET for the detectability of A beta deposition. Further, the addition of nonradiolabeled DRM106 fully blocked the binding of I-125-DRM106 and C-11-PiB, but not C-11-PBB3, to AD brain sections, and I-125-DRM106 showed a lower binding ratio of the diffuse plaque-rich lateral temporal cortex to the dense-coredeuritic plaque-rich hippocampal CA1 area, compared with C-11-PiB. Conclusion: All of these data demonstrated the high potential of I-123-DRM106 for amyloid imaging in preclinical and clinical application, and it might more preferentially detect dense-coredeuritic amyloid deposition, which is expected to be closely associated with neuropathologic changes of AD.