In memory of Allan E. Johnson.
Characterization of AZD4694, a novel fluorinated Aβ plaque neuroimaging PET radioligand
Article first published online: 13 MAY 2010
© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry
Journal of Neurochemistry
Volume 114, Issue 3, pages 784–794, August 2010
How to Cite
Juréus, A., Swahn, B.-M., Sandell, J., Jeppsson, F., Johnson, A. E., Johnström, P., Neelissen, J. A. M., Sunnemark, D., Farde, L. and Svensson, S. P. S. (2010), Characterization of AZD4694, a novel fluorinated Aβ plaque neuroimaging PET radioligand. Journal of Neurochemistry, 114: 784–794. doi: 10.1111/j.1471-4159.2010.06812.x
- Issue published online: 6 JUL 2010
- Article first published online: 13 MAY 2010
- Received February 4, 2010; revised manuscript received April 30, 2010; accepted April 30, 2010.
- Alzheimer’s disease;
- positron emission tomography;
J. Neurochem. (2010) 114, 784–794.
Positron emission tomography (PET) radioligands that bind selectively to β-amyloid plaques (Aβ) are promising imaging tools aimed at supporting the diagnosis of Alzheimer’s disease and the evaluation of new drugs aiming to modify amyloid plaque load. For extended clinical use, there is a particular need for PET tracers labeled with fluorine-18, a radionuclide with 110 min half-life allowing for central synthesis followed by wide distribution. The development of fluorinated radioligands is, however, challenging because of the lipophilic nature of aromatic fluorine, rendering fluorinated ligands more prone to have high non-specific white matter binding. We have here developed the new benzofuran-derived radioligand containing fluorine, AZD4694 that shows high affinity for β-amyloid fibrils in vitro (Kd = 2.3 ± 0.3 nM). In cortical sections from human Alzheimer’s disease brain [3H]AZD4694 selectively labeled β-amyloid deposits in gray matter, whereas there was a lower level of non-displaceable binding in plaque devoid white matter. Administration of unlabeled AZD4694 to rat showed that it has a pharmacokinetic profile consistent with good PET radioligands, i.e., it quickly entered and rapidly cleared from normal rat brain tissue. Ex vivo binding data in aged Tg2576 mice after intravenous administration of [3H]AZD4694 showed selective binding to β-amyloid deposits in a reversible manner. In Tg2576 mice, plaque bound [3H]AZD4694 could still be detected 80 min after i.v. administration. Taken together, the preclinical profile of AZD4694 suggests that fluorine-18 labeled AZD4694 may have potential for PET-visualization of cerebral β-amyloid deposits in the living human brain.