PET Imaging in Preclinical Anti-Aβ Drug Development

Syvänen, Stina; Meier, Silvio R.; Roshanbin, Sahar; Xiong, Mengfei; Faresjö, Rebecca; Gustavsson, Tobias; Bonvicini, Gillian; Schlein, Eva; Aguilar, Ximena; Julku, Ulrika; Eriksson, Jonas; Sehlin, Dag

doi:10.1007/s11095-022-03277-z

Cited by 10 publications

(3 citation statements)

References 109 publications

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“…One of the weaknesses of current clinical trials is that determining the efficacy/safety of BACE1 inhibitors largely depends on final cognitive outputs (i.e., lack of biomarker-based end points). Further study is required to establish blood-based biomarkers such as Aβ42 elevations (Botella Lucena et al, 2022) and Aβ PET imaging analysis in defined brain structures (Syvänen et al, 2022) that are closely associated with the occurrence of ALF and its rescue with BACE1 inhibitors. Undoubtedly, more work also needs to be done to better understand the mechanisms of cognitive worsening and identify the underlying substrates that can serve as markers to track side effects of overdosed BACE1 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Accelerated long-term forgetting: A sensitive paradigm for detecting subtle cognitive impairment and evaluating BACE1 inhibitor efficacy in preclinical Alzheimer's disease

Ohno¹

2023

Front. Dement.

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Given a long preclinical stage of Alzheimer's disease (AD) continuum before the onset of dementia, there is a growing demand for tools capable of detecting the earliest feature of subtle cognitive impairment and optimizing recruitment to clinical trials for potentially disease-modifying therapeutic interventions such as BACE1 inhibitors. Now that all BACE1 inhibitor programs in symptomatic and prodromal AD populations have ended in failure, trials need to shift to target the earlier preclinical stage. However, evaluating cognitive efficacy (if any) in asymptomatic AD individuals is a great challenge. In this context, accelerated long-term forgetting (ALF) is emerging as a sensitive cognitive measure that can discriminate between presymptomatic individuals with high risks for developing AD and healthy controls. ALF is characterized by increased forgetting rates over extended delays (e.g., days, weeks, months) despite normal learning and short-term retention on standard memory assessments that typically use around 30-min delays. This review provides an overview of recent progress in animal model and clinical studies on this topic, focusing on the utility and underlying mechanism of ALF that may be applicable to earlier diagnosis and BACE1 inhibitor efficacy evaluation at a preclinical stage of AD.

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Section: Discussionmentioning

confidence: 99%

Accelerated long-term forgetting: A sensitive paradigm for detecting subtle cognitive impairment and evaluating BACE1 inhibitor efficacy in preclinical Alzheimer's disease

Ohno¹

2023

Front. Dement.

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“…Antibodies are highly specific to their target and are therefore attractive tools to be used in functional imaging. Their specificity to their epitope allows for the distinction of various aggregation entities of amyloid-beta (Aβ), (Magnusson et al 2013 ; Sehlin et al 2017 ; Syvänen et al 2022 ; Sehlin et al 2019 ) which can open up new possibilities for immune imaging, including the specific targeting of soluble or diffuse Aβ aggregates. The recent approval of the therapeutic Aβ antibody Lecanemab (Dyck et al 2023 ) has increased the need for relevant immune tracers for target screening and treatment monitoring.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET

Schlein,

Rokka,

Odell

et al. 2024

EJNMMI radiopharm. chem.

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Background The brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood–brain barrier (BBB). To overcome this physiological obstacle, we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. While these radiolabelled ligands have high affinity and specificity, their long residence time in the blood and brain, typical for large molecules, poses another challenge for PET imaging. A viable solution could be a two-step pre-targeting approach which involves the administration of a tagged antibody that accumulates at the target site in the brain and then clears from the blood, followed by administration of a small radiolabelled molecule with fast kinetics. This radiolabelled molecule can couple to the tagged antibody and thereby make the antibody localisation visible by PET imaging. The in vivo linkage can be achieved by using the inverse electron demand Diels–Alder reaction (IEDDA), with trans-cyclooctene (TCO) and tetrazine groups participating as reactants. In this study, two novel 18F-labelled tetrazines were synthesized and evaluated for their potential use as pre-targeting imaging agents, i.e., for their ability to rapidly enter the brain and, if unbound, to be efficiently cleared with minimal background retention. Results The two compounds, a methyl tetrazine [18F]MeTz and an H-tetrazine [18F]HTz were radiolabelled using a two-step procedure via [18F]F-Py-TFP synthesized on solid support followed by amidation with amine-bearing tetrazines, resulting in radiochemical yields of 24% and 22%, respectively, and a radiochemical purity of > 96%. In vivo PET imaging was performed to assess their suitability for in vivo pre-targeting. Time-activity curves from PET-scans showed [18F]MeTz to be the more pharmacokinetically suitable agent, given its fast and homogenous distribution in the brain and rapid clearance. However, in terms of rection kinetics, H-tetrazines are advantageous, exhibiting faster reaction rates in IEDDA reactions with dienophiles like trans-cyclooctenes, making [18F]HTz potentially more beneficial for pre-targeting applications. Conclusion This study demonstrates a significant potential of [18F]MeTz and [18F]HTz as agents for pre-targeted PET brain imaging due to their efficient brain uptake, swift clearance and appropriate chemical stability.

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“…For example, lecanemab is primarily directed toward protofibrillar Aβ ( 6 , 10 ). Thus, despite the successful use of brain imaging in the recent development of antibody-based therapies, there is a mismatch between the imaging target and treatment target ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Indium-111 radiolabelling of a brain-penetrant Aβ antibody for SPECT imaging

Gustavsson,

Herth,

Sehlin

et al. 2024

ujms

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Background: The development of bispecific antibodies that can traverse the blood–brain barrier has paved the way for brain-directed immunotherapy and when radiolabelled, immunoPET imaging. The objective of this study was to investigate how indium-111 (111In) radiolabelling with compatible chelators affects the brain delivery and peripheral biodistribution of the bispecific antibody RmAb158-scFv8D3, which binds to amyloid-beta (Aβ) and the transferrin receptor (TfR), in Aβ pathology-expressing tg-ArcSwe mice and aged-matched wild-type control mice. Methods: Bispecific RmAb158-scFv8D3 (biAb) was radiolabelled with 111In using CHX-A”-DTPA, DOTA, or DOTA-tetrazine (DOTA-Tz). Affinity toward TfR and Aβ, as well as stability, was investigated in vitro. Mice were then intravenously administered with the three different radiolabelled biAb variants, and blood samples were collected for monitoring pharmacokinetics. Brain concentration was quantified after 2 and 72 h, and organ-specific retention was measured at 72 h by gamma counting. A subset of mice also underwent whole-body Single-photon emission computed tomography (SPECT) scanning at 72 h after injection. Following post-mortem isolation, the brains of tg-ArcSwe and WT mice were sectioned, and the spatial distribution of biAb was further investigated with autoradiography. Results: All three [111In]biAb variants displayed similar blood pharmacokinetics and brain uptake at 2 h after administration. Radiolabelling did not compromise affinity, and all variants showed good stability, especially the DOTA-Tz variant. Whole-body SPECT scanning indicated high liver, spleen, and bone accumulation of all [111In]biAb variants. Subsequent ex vivo measurement of organ retention confirmed SPECT data, with retention in the spleen, liver, and bone – with very high bone marrow retention. Ex vivo gamma measurement of brain tissue, isolated at 72 h post-injection, and ex vivo autoradiography showed that WT mice, despite the absence of Aβ, exhibited comparable brain concentrations of [111In]biAb as those found in the tg-ArcSwe brain. Conclusions: The successful 111In-labelling of biAb with retained binding to TfR and Aβ, and retained ability to enter the brain, demonstrated that 111In can be used to generate radioligands for brain imaging. A high degree of [111In]biAb in bone marrow and intracellular accumulation in brain tissue indicated some off-target interactions or potential interaction with intrabrain TfR resulting in a relatively high non-specific background signal.

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PET Imaging in Preclinical Anti-Aβ Drug Development

Cited by 10 publications

References 109 publications

Accelerated long-term forgetting: A sensitive paradigm for detecting subtle cognitive impairment and evaluating BACE1 inhibitor efficacy in preclinical Alzheimer's disease

Accelerated long-term forgetting: A sensitive paradigm for detecting subtle cognitive impairment and evaluating BACE1 inhibitor efficacy in preclinical Alzheimer's disease

Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET

Indium-111 radiolabelling of a brain-penetrant Aβ antibody for SPECT imaging

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