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

UNLABELLED: Noninvasive determination of amyloid-ß peptide (Aß) 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 ((123/125)I-DRM106 [6-iodo-2-[4-(1H-3-pyrazolyl)phenyl]imidazo[1,2-a]pyridine]), a compound with sufficient affinity for the synthesis of human Aß fibrils and satisfactory metabolic stability, as a SPECT ligand in living brains. METHOD: The sensitivity of (125)I-DRM106 for detecting Aß deposition was compared with that of (125)I-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 Aß plaques with (123)I-DRM106 and a well-known amyloid PET agent, (11)C-labeled Pittsburgh compound B ((11)C-PiB), in 29-mo-old transgenic mice and age-matched nontransgenic littermates. Additionally, we compared the binding characteristics of (125)I-DRM106 with those of (11)C-PiB and (11)C-PBB3, which selectively bind to Aß plaques and preferentially to tau aggregates, respectively, in postmortem AD brain sections. RESULTS: Ex vivo autoradiographic analysis showed that measurement with (125)I-DRM106 has a higher sensitivity for detecting Aß accumulation than with (125)I-IMPY in transgenic mice. SPECT imaging with (123)I-DRM106 also successfully detected Aß deposition in living aged transgenic mice and showed strong correlation (R = 0.95, P < 0.01) in quantitative analysis for Aß plaque detection by PET imaging with (11)C-PiB, implying that sensitivity and quantitation of SPECT imaging with (123)I-DRM106 are almost as good as (11)C-PiB PET for the detectability of Aß deposition. Further, the addition of nonradiolabeled DRM106 fully blocked the binding of (125)I-DRM106 and (11)C-PiB, but not (11)C-PBB3, to AD brain sections, and (125)I-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 (11)C-PiB. CONCLUSION: All of these data demonstrated the high potential of (123)I-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.

(123)I- or (125)I-metaiodobenzylguanidine visualization of brown adipose tissue.

UNLABELLED: (123)I-Metaiodobenzylguanidine (MIBG) accumulations that do not correspond to any tumor are observed occasionally on the medial aspect of the upper back or shoulder of children. The true nature of such accumulations is unknown, and we hypothesized that they represent interscapular brown adipose tissue (IBAT) visualized by scintigraphy. METHODS: Wistar rats (7 wk old) received MIBG labeled with (123)I or (125)I. Autoradiography was performed, and concentrations of the tracer in the interscapular subcutaneous tissue were identified histopathologically. The effects of 6-hydroxydopamine, reserpine, and beta 3-adrenergic receptor agonist (CL316,243) on the accumulation were investigated to elucidate the mechanism of uptake into BAT. RESULTS: Autoradiography showed well-defined distinct accumulation in the subcutaneous tissue on the upper back, and hematoxylin-eosin and anti-uncoupling protein 1 antibody staining confirmed that it was BAT. The percentage injected dose per gram in BAT was as high as that in the heart and was quite different from the concentration in white adipose tissue. Preadministration of 6-hydroxydopamine or reserpine resulted in lower MIBG concentrations in BAT. Activation of the beta 3-adrenergic receptor accelerated the washout of MIBG in BAT and caused an increase in concentration in white adipose tissue. CONCLUSION: MIBG accumulates in the adrenergic nervous system in BAT, and IBAT is distinguished from the surrounding white adipose tissue. To our knowledge, BAT has not been visualized previously. We showed that MIBG scintigraphy might be suitable for the investigation of BAT and treatment of human obesity.

Biological evaluation of the radioiodinated imidazo[1,2-a]pyridine derivative DRK092 for amyloid-ß imaging in mouse model of Alzheimer's disease.

Non-invasive determination of amyloid-ß peptide (Aß) deposition has important significance for early diagnosis and medical intervention in Alzheimer's disease (AD). In this study, we investigated the availability of a radioiodinated imidazo[1,2-a]pyridine derivative, termed (125)I-DRK092, as single photon emission computed tomography (SPECT) ligand for in vivo detection of Aß deposition. DRK092 showed high binding affinity for either synthetic human Aß fibrils or brain homogenates from amyloid precursor protein transgenic (Tg) mouse (PS1-ki/JU-Tg2576) and AD patient with a dissociation constant (Kd) of one-digit nM, and excellent brain permeability (peak value of uptake: approximately 0.9% of injection dose/g rat brain). Ex vivo autoradiographic analysis showed that measurement with (125)I-DRK092 has higher sensibility for detecting Aß accumulation than with (125)I-IMPY, a well-known amyloid SPECT ligand, in Tg mice. In vitro autoradiography with (125)I-DRK092 also confirmed higher accumulation of radioactivity in the cortical area, enriched with Aß plaques, of Tg mouse and AD patient brains, as compared with the corresponding areas in non-Tg mouse and healthy control brains. All the data presented above lead us to draw the conclusion that radioiodinated DRK092 is a potential SPECT ligand for amyloid imaging in AD.