Clinical Validation of ¹⁸F-AZD4694, an Amyloid-β–Specific PET Radioligand

Abstract

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...

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

“…In general, this white matter uptake has been described to be less pronounced for [ 11 C]PiB as compared to the 18 F labeled compounds, which may somewhat decrease the sensitivity of the 18 Flabeled versions of amyloid tracers. The tracer 18 F-AZD4694 may form an exception, because it has been demonstrated to show comparably lower white matter retention [269]. The apparent differences in tracer distribution between different types of amyloid tracers have raised concerns about the comparability/ standardization of amyloid-PET results.…”

Quantification of Blood Flow-Dependent Component in Estimates of Beta-Amyloid Load Obtained Using Quasi-Steady-State Standardized Uptake Value Ratio

“…20,21 This phase is characterized by a gradual wash-out of radioactivity from both target and reference regions and the time curve for the ratio of radioactivity between target and reference regions is almost stable though with a slight positive slope for several radioligands. [22][23][24][25][26] The SUVR value is viewed as an index for specific binding and its proportionality to the distribution volume ratio (DVR), obtained using fully quantitative PET acquisition and analysis, has been shown for several amyloid radioligands. [22][23][24]26 However, the quasi-steady-state SUVR values are biased in the sense that they overestimate DVR as the time window of acquisition occurs after the peak time of specific binding.…”

“…[22][23][24][25][26] The SUVR value is viewed as an index for specific binding and its proportionality to the distribution volume ratio (DVR), obtained using fully quantitative PET acquisition and analysis, has been shown for several amyloid radioligands. [22][23][24]26 However, the quasi-steady-state SUVR values are biased in the sense that they overestimate DVR as the time window of acquisition occurs after the peak time of specific binding. 20,27 For amyloid radioligands, the overestimation by quasi-steady-state SUVR has been estimated to be 30% to 70%.…”

Amyloid Imaging: Poised for Integration into Medical Practice

“…Initial in vitro studies demonstrated the high affinity of this compound for Aβ with less binding in the white matter [49]. Further, clinical trials demonstrated the ability of NAV4694 to discriminate between clinically diagnosed patients with AD and normal control subjects with a high degree of test-retest concordance using the reference Logan approach [50]. As a standard for comparison, a study with 25 controls, 10 patients with MCI, 7 with probable AD, and 3 with probable frontotemporal dementia underwent scans with PIB and NAV4694, with similar regions of interests identified on both scans.…”