Pioneered with the invention of 11 C-Pittsburgh compound B, amyloid-b imaging using PET has facilitated research in Alzheimer disease (AD). This imaging approach has promise for diagnostic purposes and evaluation of disease-modifying therapies. Broad clinical use requires an 18 F-labeled amyloid-b radioligand with high specific and low nonspecific binding. The aim of the present PET study was to examine the radioligand 18 F-AZD4694 in human subjects. Methods: Six control subjects and 10 clinically diagnosed AD patients underwent PET examination with 18 F-AZD4694 and a structural MRI scan. Of these, 4 controls and 4 patients underwent a second PET examination for test-retest analysis. Arterial sampling was done to derive a metabolite-corrected plasma input function for traditional compartment modeling. Besides, several simplified quantitative approaches were applied, including the reference Logan approach and simple ratio methods. Results: After intravenous injection of 18 F-AZD4694, radioactivity appeared rapidly in brain. In patients, radioactivity was high in regions expected to contain amyloid-b, whereas in controls, radioactivity was low and homogenously distributed. Binding in cerebellum, a reference region, was low and similar between the groups. Specific binding was reversible and peaked at about 27 min after injection in regions with high radioactivity. The time-activity curves could be described using the 2-tissuecompartment model. Distribution volume ratio estimates obtained using compartment models and simplified methods were highly correlated. Standardized uptake value ratios calculated at late times and distribution volume ratios estimated with the reference Logan approach were, in gray matter, significantly lower in control subjects (1. Al zheimer disease (AD) was identified more than a century ago on the basis of histopathologic observations. The diagnosis of AD, however, is a clinical challenge, and a definite diagnosis can still only be made after death. In clinical research on AD, the search for sensitive and specific in vivo biomarkers has thus been given high priority. A promising recent approach is the use of PET and radiolabeled ligands targeting amyloid-b deposits in the brain. The first and so-far most successful radioligand is 11 C-labeled 2-[49-(methylamino) phenyl]-6-hydroxybenzothiazole ( 11 C-PIB), which binds predominantly to amyloid-b plaques in the human brain (1). Initial studies have shown that control subjects (CSs) and AD patients can be separated on the basis of their amyloid-b load (2). Subsequently, in vivo amyloid-b imaging has been applied in research on early AD diagnosis (3), evaluation of longitudinal progression of disease (4), and evaluation of new disease-modifying therapies (5).This first generation of amyloid-b radioligands has thereby opened a new field of neuroimaging research. Radioligands such as 11 C-PIB have affinity for amyloid-b in the low-nanomolar range, and a favorable near-stable signal-to-background ratio is obtained during the later phase of data acq...

11 C-Pittsburgh compound-B ( 11 C-PiB) is the benchmark radiotracer for imaging of b-amyloid (Ab) plaque in Alzheimer disease (AD). 18 F-labeled Ab tracers subsequently developed for clinical use show higher nonspecific white matter binding and, in some cases, lower cortical binding in AD that could lead to less accurate interpretation of scans. We compared the cortical and white matter binding of a new 18 F-labeled Ab tracer, 18 F-AZD4694 (recently renamed NAV4694), with 11 C-PiB in the same subjects. Methods: Forty-five participants underwent PET imaging with 11 C-PiB and 18 F-AZD4694 (25 healthy elderly controls [HCs], 10 subjects with mild cognitive impairment, 7 subjects with probable AD, and 3 subjects with probable frontotemporal dementia). Images were coregistered so that region-ofinterest placement was identical on both scans, and standardized uptake value ratios (SUVRs) using the cerebellar cortex as a reference region were calculated between 40 and 70 min after injection for both tracers. Results: 18 F-AZD4694 showed reversible binding kinetics similar to 11 C-PiB, reaching an apparent steady state at 50 min after injection. Both radiotracers showed a similar dynamic range of neocortical SUVR (1.1-3.3 and 1.0-3.2 SUVR for 11 C-PiB and 18 F-AZD4694, respectively) and identical low nonspecific white matter binding, with frontal cortex-to-white matter ratios of 0.7 6 0.2 and 1.3 6 0.2 for both radiotracers in HCs and AD subjects, respectively. There was an excellent linear correlation between 11 C-PiB and 18 F-AZD4694 neocortical SUVR (slope of 0.95, r 5 0.99, P , 0.0001). Conclusion: 18 F-AZD4694 displays imaging characteristics nearly identical to those of 11 C-PiB. The low white matter and high cortical binding in AD indicate that this tracer is well suited to both clinical and research use.

The presence of β‐amyloid plaques in brain is a hallmark of Alzheimer’s disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Positron emission tomography (PET) radioligands such as Pittsburgh compound B ([11C]‐2‐(3‐fluoro‐4‐methylamino‐phenyl)‐benzothiazol‐6‐ol) (PIB) binds selectively to β‐amyloid and are promising new tools supporting the clinical diagnoses of AD. In addition, such methodology may be useful for evaluation of new drugs aiming at reduction of amyloid plaque load. The objective of this study is to develop a new amyloid selective PET radioligand with higher signal‐to‐background ratio when compared with existing amyloid PET ligands. The lead compound, AZD2184, (2‐[6‐(methylamino)pyridin‐3‐yl]‐1,3‐benzothiazol‐6‐ol) was found to have high affinity for amyloid fibrils in vitro (Kd: 8.4 ± 1.0 nM). Two minutes after i.v. administration in rats, about 1% of the dose was in brain. In vitro autoradiography on cortical brain sections from amyloid‐beta precursor protein/presenilin 1 (APP/PS1) mice and AD patients showed that while [3H]AZD2184 and [3H]PIB are mutually displaceable, [3H]AZD2184 displays a higher signal‐to‐background ratio primarily by virtue of lower background binding levels. The ratio of binding ability in prefrontal cortex (high plaque load) to subcortical white matter (background) was 4.5 for [3H]AZD2184 and 0.8 for [3H]PIB at 1 nM. In adjacent cortical sections from APP/PS1 mouse as well as from AD cortical tissue, [3H]AZD2184 and antibodies to human β‐amyloid labeled identical structures. In vivo administration of [3H]AZD2184 to APP/PS1 mice further showed that [3H]AZD2184 labels amyloid deposits with low non‐specific background binding. Taken together, the pre‐clinical profile of AZD2184 in relation to the reference ligand PIB, suggests that 11C‐labeled AZD2184 is a potential radioligand for PET‐visualization of β‐amyloid deposits in the living human brain.

J. Neurochem. (2010) 114, 784–794. Abstract 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.

The success of future intervention strategies for Alzheimer’s disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.