Development of Brain-penetrable Antibody Radioligands for PET Imaging of Amyloid-β and Tau

Overview

Journal Front Nucl Med

Date 2023 Sep 8

PMID 37680310

Authors

Vinay Banka

Andrew Kelleher

Dag Sehlin

Greta Hultqvist

Einar M Sigurdsson

Stina Syvanen

Yu-Shin Ding

Affiliations

Soon will be listed here.

Abstract

Introduction: Alzheimer's disease (AD) is characterized by the misfolding and aggregation of two major proteins: amyloid-beta (Aβ) and tau. Antibody-based PET radioligands are desirable due to their high specificity and affinity; however, antibody uptake in the brain is limited by the blood-brain barrier (BBB). Previously, we demonstrated that antibody transport across the BBB can be facilitated through interaction with the transferrin receptor (TfR), and the bispecific antibody-based PET ligands were capable of detecting Aβ aggregates via imaging. Since tau accumulation in the brain is more closely correlated with neuronal death and cognition, we report here our strategies to prepare four F-18-labeled specifically engineered bispecific antibody probes for the selective detection of tau and Aβ aggregates to evaluate their feasibility and specificity, particularly for PET imaging.

Methods: We first created and evaluated (via both and studies) four specifically engineered bispecific antibodies, by fusion of single-chain variable fragments (scFv) of a TfR antibody with either a full-size IgG antibody of Aβ or tau or with their respective scFv. Using [F]SFB as the prosthetic group, all four F-labeled bispecific antibody probes were then prepared by conjugation of antibody and [F]SFB in acetonitrile/0.1 M borate buffer solution (final pH ~ 8.5) with an incubation of 20 min at room temperature, followed by purification on a PD MiniTrap G-25 size exclusion gravity column.

Results: Based on both and evaluation, the bispecific antibodies displayed much higher brain concentrations than the unmodified antibody, supporting our subsequent F18-radiolabeling. [F]SFB was produced in high yields in 60 min (decay-corrected radiochemical yield (RCY) 46.7 ± 5.4) with radiochemical purities of >95%, confirmed by analytical high performance liquid chromatography (HPLC) and radio-TLC. Conjugation of [F]SFB and bispecific antibodies showed a 65%-83% conversion efficiency with radiochemical purities of 95%-99% by radio-TLC.

Conclusions: We successfully labeled four novel and specifically engineered bispecific antibodies with [F]SFB under mild conditions with a high RCY and purities. This study provides strategies to create brain-penetrable F-18 radiolabeled antibody probes for the selective detection of tau and Aβ aggregates in the brain of transgenic AD mice via PET imaging.

Citing Articles

Feasibility of F-18 radiolabeled brain-penetrable bi-specific antibody radioligands for PET imaging of tauopathy.

Kelleher A, Richardson B, Kumar Banka V, Kazior A, Tan C, Chan S RSC Med Chem. 2025; .

PMID: 40008191 PMC: 11848619. DOI: 10.1039/d4md00866a.

[I]IPC-Lecanemab: Synthesis and Evaluation of Aβ-Plaque-Binding Antibody and Comparison with Small-Molecule [F]Flotaza and [I]IBETA in Postmortem Human Alzheimer's Disease.

Liang C, Paclibar C, Gonzaga N, Sison S, Bath H, Biju A Neurol Int. 2024; 16(2):419-431.

PMID: 38668128 PMC: 11054302. DOI: 10.3390/neurolint16020031.

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