Aβ1-40 Peptide Radiopharmaceuticals for Brain Amyloid Imaging: 111In Chelation, Conjugation to Poly(ethylene glycol)-Biotin Linkers, and Autoradiography with Alzheimer's Disease Brain Sections

Publisher Website
Google Scholar
Abstract
The amyloid plaques of Alzheimer's disease (AD) are formed by the neuropeptide Aβ1-42/43, and carboxyl terminal truncated forms of this neuropeptide, designated Aβ1-40, bind to amyloid plaques of AD autopsy tissue sections. Therefore, Aβ1-40 is a potential peptide radiopharmaceutical that could be used for imaging brain amyloid in living subjects with AD, should this neuropeptide be made transportable through the blood-brain barrier (BBB). To accomplish this, the neuropeptide must be modified to enable (i) attachment to a BBB drug targeting system and (ii) labeling with a radionuclide, e.g., 111-indium, suitable for brain imaging by external detection modalities such as single photon emission computed tomography (SPECT). The present studies describe the synthesis of an Aβ1-40 analogue that contains a biotin at the amino terminus and a diethylenetriaminepentaacetic acid (DTPA) moiety conjugated to one of the internal lysine residues. The DTPA-[N-biotin]-Aβ1-40 was purified by gel filtration fast-protein liquid chromatography (FPLC) using two Superose 12HR columns in series, and the structure of the purified peptide was confirmed by matrix-assisted laser desorption ionization (MALDI) mass spectrometry. The binding of the [111In]DTPA-[N-biotin]-Aβ1-40 to amyloid plaques of AD autopsy tissue sections was demonstrated by film and emulsion autoradiography. A poly(ethylene glycol) (PEG) linker of 3400 Da molecular mass, designated PEG3400, was inserted between the Aβ1-40 and the biotin moiety, but this modification diminishes binding of Aβ1-40 to the AD amyloid plaques. In summary, these studies describe a novel formulation of biotinylated Aβ1-40 that allows radiolabeling with 111-indium. The peptide radiopharmaceutical may be conjugated to an avidin-based BBB drug targeting system to enable transport through the BBB and imaging of brain amyloid in vivo.