Positron emission tomography (PET) radioligands that bind selectively to
beta-amyloid plaques (Abeta) 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
beta-amyloid fibrils in vitro (K(d) = 2.3 +/- 0.3 nM). In cortical sections from human
Alzheimer's disease brain [(3)H]
AZD4694 selectively labeled
beta-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 [(3)H]
AZD4694 showed selective binding to
beta-amyloid deposits in a reversible manner. In Tg2576 mice, plaque bound [(3)H]
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
beta-amyloid deposits in the living human brain.