Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients.

Abstract

PURPOSE:

The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD).

METHODS:

In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients.

RESULTS:

AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus.

CONCLUSION:

Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.

• Authors: Anton Forsberg, Anders Juréus, Zsolt Cselényi, Maria Eriksdotter, Yvonne Freund-Levi, Fredrik Jeppsson, Britt-Marie Swahn, Johan Sandell, Per Julin, Magnus Schou, Jan Andersson, Peter Johnström, Katarina Varnäs, Christer Halldin, Lars Farde, Samuel Svensson
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 40 Issue 4 Pg. 580-93 (Apr 2013) ISSN: 1619-7089 [Electronic] Germany
• PMID: 23324871 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
• 2-(6-(methylamino)pyridin-3-yl)-1,3-benzothiazol-6-ol
• AZD2995
• Aminopyridines
• Amyloid beta-Peptides
• Aniline Compounds
• Benzothiazoles
• Benzoxazoles
• Carbon Radioisotopes
• Radiopharmaceuticals
• Thiazoles

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (diagnosis, diagnostic imaging, genetics)
• Aminopyridines (pharmacokinetics)
• Amyloid beta-Peptides (analysis)
• Aniline Compounds
• Animals
• Benzothiazoles (pharmacokinetics)
• Benzoxazoles (pharmacokinetics)
• Binding Sites
• Brain (diagnostic imaging)
• Carbon Radioisotopes
• Case-Control Studies
• Female
• Humans
• Magnetic Resonance Imaging
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• Positron-Emission Tomography
• Protein Binding
• Radioligand Assay
• Radiopharmaceuticals (pharmacokinetics)
• Sensitivity and Specificity
• Thiazoles