Clinical validation of 18F-AZD4694, an amyloid-β-specific PET radioligand.
Pioneered with the invention of (11)C-Pittsburgh compound B, amyloid-β 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-β 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-β, 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-tissue-compartment 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 (1.08 [11%] and 1.01 [6%], respectively) than in AD patients (2.15 [24%] and 1.62 [18%], respectively). Among noninvasive methods, the lowest test-retest variability was found with reference Logan, varying between 4% and 6% across brain regions.


CONCLUSIONS
Noninvasive quantitative approaches provide valid estimates of amyloid-β binding. Because of the radioisotope ((18)F) used for labeling, the radioligand has potential for wide clinical application. (18)F-AZD4694 satisfies the requirements for a promising amyloid-β radioligand both for diagnostic use and for evaluation of disease-modifying therapies in AD.
Neuroscience Research and Therapy Area, AstraZeneca Research and Development, Södertälje, Sweden. zsolt.cselenyi@astrazeneca.com
Zsolt
Z
Cselényi
Maria Eriksdotter
ME
Jönhagen
Anton
A
Forsberg
Christer
C
Halldin
Per
P
Julin
Magnus
M
Schou
Peter
P
Johnström
Katarina
K
Varnäs
Samuel
S
Svensson
Lars
L
Farde
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001158:Arteries / Q000000981:diagnostic imaging; D001572:Benzofurans / Q000493:pharmacokinetics*; D002560:Cerebrovascular Circulation; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics*; D007091:Image Processing, Computer-Assisted; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D015203:Reproducibility of Results
C552498:AZD4694; D016229:Amyloid beta-Peptides; D001572:Benzofurans; D006845:Hydrocarbons, Fluorinated; D019275:Radiopharmaceuticals