In vivo SPECT imaging of amyloid-β deposition with radioiodinated imidazo[1, 2-α]pyridine derivative DRM106 in a mouse model of alzheimer's disease

Noninvasive determination of amyloid-β peptide (Aβ) 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 (^123/125I-DRM106 [6-iodo-2- [4-(1H-3-pyrazolyl)phenyl]imidazo[1, 2-a]pyridine]), a compound with sufficient affinity for the synthesis of human Aβ fibrils and satisfactory metabolic stability, as a SPECT ligand in living brains. Method: The sensitivity of ¹²⁵I-DRM106 for detecting Aβ deposition was compared with that of ¹²⁵I-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 Aβ plaques with ¹²³I-DRM106 and a well-known amyloid PET agent, ¹¹C-labeled Pittsburgh compound B (¹¹C-PiB), in 29-mo-old transgenic mice and age-matched nontransgenic littermates. Additionally, we compared the binding characteristics of ¹²⁵I-DRM106 with those of ¹¹C-PiB and ¹¹C-PBB3, which selectively bind to Aβ plaques and preferentially to tau aggregates, respectively, in postmortem AD brain sections.

Results: Ex vivo autoradiographic analysis showed that measurement with ¹²⁵I-DRM106 has a higher sensitivity for detecting Aβ accumulation than with ¹²⁵I-IMPY in transgenic mice. SPECT imaging with ¹²³I-DRM106 also successfully detected Aβ deposition in living aged transgenic mice and showed strong correlation (R 5 0.95, P , 0.01) in quantitative analysis for Aβ plaque detection by PET imaging with ¹¹C-PiB, implying that sensitivity and quantitation of SPECT imaging with ¹²³I-DRM106 are almost as good as ¹¹C-PiB PET for the detectability of Aβ deposition. Further, the addition of nonradiolabeled DRM106 fully blocked the binding of ¹²⁵I-DRM106 and ¹¹C-PiB, but not ¹¹C-PBB3, to AD brain sections, and ¹²⁵I-DRM106 showed a lower binding ratio of the diffuse plaque-rich lateral temporal cortex to the dense-cored/neuritic plaque-rich hippocampal CA1 area, compared with ¹¹C-PiB.

Conclusion: All of these data demonstrated the high potential of ¹²³I-DRM106 for amyloid imaging in preclinical and clinical application, and it might more preferentially detect dense-cored/neuritic amyloid deposition, which is expected to be closely associated with neuropathologic changes of AD.