Antibody-Based In Vivo PET Imaging Detects Amyloid-β Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition.

Visualization of amyloid-β (Aβ) pathology with PET has become an important tool for making a specific clinical diagnosis of Alzheimer disease (AD). However, the available amyloid PET radioligands, such as 11C-Pittsburgh compound B, reflect levels of insoluble Aβ plaques but do not capture soluble and protofibrillar Aβ forms. Furthermore, the plaque load appears to be fairly static during clinical stages of AD and may not be affected by Aβ-reducing treatments. The aim of the present study was to investigate whether a novel PET radioligand based on an antibody directed toward soluble aggregates of Aβ can be used to detect changes in Aβ levels during disease progression and after treatment with a β-secretase (BACE-1) inhibitor. Methods: One set of transgenic mice (tg-ArcSwe, a model of Aβ pathology) aged between 7 and 16 mo underwent PET with the Aβ protofibril-selective radioligand 124I-RmAb158-scFv8D3 (where RmAb is recombinant mouse monoclonal antibody and scFv is single-chain variable fragment) to follow progression of Aβ pathology in the brain. A second set of tg-ArcSwe mice, aged 10 mo, were treated with the BACE-1 inhibitor NB-360 for 3 mo and compared with an untreated control group. A third set of tg-ArcSwe mice, also aged 10 mo, underwent PET as a baseline group. Brain tissue was isolated after PET to determine levels of Aβ by ELISA and immunohistochemistry. Results: The concentration of 124I-RmAb158-scFv8D3, as measured in vivo with PET, increased with age and corresponded well with the ex vivo autoradiography and Aβ immunohistochemistry results. Mice treated with NB-360 showed significantly lower in vivo PET signals than untreated animals and were similar to the baseline animals. The decreased 124I-RmAb158-scFv8D3 concentrations in NB-360-treated mice, as quantified with PET, corresponded well with the decreased Aβ levels measured in postmortem brain. Conclusion: Several treatments for AD are in phase 2 and 3 clinical trials, but the possibility of studying treatment effects in vivo on the important, nonfibrillar, forms of Aβ is limited. This study demonstrated the ability of the Aβ protofibril-selective radioligand 124I-RmAb158-scFv8D3 to follow disease progression and detect treatment effects with PET imaging in tg-ArcSwe mice.

Meier SR ，Syvänen S ，Hultqvist G ，Fang XT ，Roshanbin S ，Lannfelt L ，Neumann U ，Sehlin D ... -  《-》

(11)C-PiB and (124)I-Antibody PET Provide Differing Estimates of Brain Amyloid-β After Therapeutic Intervention.

PET imaging of amyloid-β (Aβ) has become an important component of Alzheimer disease diagnosis. 11C-Pittsburgh compound B (11C-PiB) and analogs bind to fibrillar Aβ. However, levels of nonfibrillar, soluble, aggregates of Aβ appear more dynamic during disease progression and more affected by Aβ-reducing treatments. The aim of this study was to compare an antibody-based PET ligand targeting nonfibrillar Aβ with 11C-PiB after β-secretase (BACE-1) inhibition in 2 Alzheimer disease mouse models at an advanced stage of Aβ pathology. Methods: Transgenic ArcSwe mice (16 mo old) were treated with the BACE-1 inhibitor NB-360 for 2 mo, whereas another group was kept as controls. A third group was analyzed at the age of 16 mo as a baseline. Mice were PET-scanned with 11C-PiB to measure Aβ plaque load followed by a scan with the bispecific radioligand 124I-RmAb158-scFv8D3 to investigate nonfibrillar aggregates of Aβ. The same study design was then applied to another mouse model, AppNL-G-F In this case, NB-360 treatment was initiated at the age of 8 mo and animals were scanned with 11C-PiB-PET and 125I-RmAb158-scFv8D3 SPECT. Brain tissue was isolated after scanning, and Aβ levels were assessed. Results: 124I-RmAb158-scFv8D3 concentrations measured with PET in hippocampus and thalamus of NB-360-treated ArcSwe mice were similar to those observed in baseline animals and significantly lower than concentrations observed in same-age untreated controls. Reduced 125I-RmAb158-scFv8D3 retention was also observed with SPECT in hippocampus, cortex, and cerebellum of NB-360-treated AppNL-G-F mice. Radioligand in vivo concentrations corresponded to postmortem brain tissue analysis of soluble Aβ aggregates. For both models, mice treated with NB-360 did not display a reduced 11C-PiB signal compared with untreated controls, and further, both NB-360 and control mice tended, although not reaching significance, to show higher 11C-PiB signal than the baseline groups. Conclusion: This study demonstrated the ability of an antibody-based radioligand to detect changes in brain Aβ levels after anti-Aβ therapy in ArcSwe and AppNL-G-F mice with pronounced Aβ pathology. In contrast, the decreased Aβ levels could not be quantified with 11C-PiB PET, suggesting that these ligands detect different pools of Aβ.

Meier SR ，Sehlin D ，Roshanbin S ，Falk VL ，Saito T ，Saido TC ，Neumann U ，Rokka J ，Eriksson J ，Syvänen S ... -  《-》

Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody.

Syvänen S ，Hultqvist G ，Gustavsson T ，Gumucio A ，Laudon H ，Söderberg L ，Ingelsson M ，Lannfelt L ，Sehlin D ... -  《Alzheimers Research & Therapy》

A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice.

Neumann U ，Rueeger H ，Machauer R ，Veenstra SJ ，Lueoend RM ，Tintelnot-Blomley M ，Laue G ，Beltz K ，Vogg B ，Schmid P ，Frieauff W ，Shimshek DR ，Staufenbiel M ，Jacobson LH ... -  《Molecular Neurodegeneration》

SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer's disease.

Gustavsson T ，Syvänen S ，O'Callaghan P ，Sehlin D ... -  《Translational Neurodegeneration》