AN UPDATE ON THE BINDING PROFILE OF FLORTAUCIPIR IN AD VERSUS NORMAL CNS PROTEINS AND NORMAL BRAIN

Abstract

This presentation updates the binding profile of Flortaucipir (18F) (AKA [18F]AV-1451, [18F]T807) to AD brain derived PHF tau and 72 normal CNS proteins. On and off-target binding to AD and normal brain tissue is also presented. Flortaucipir was evaluated in functional competitive binding assays against a panel of 72 normal CNS proteins. Binding studies were carried out with AD brain derived PHF tau as well as AD and normal brain homogenates. Autoradiography (ARG) was performed with 20 μCi Flortaucipir (18F) in frozen brain sections, which were then exposed with FujiFilm Imaging Plates overnight and scanned with FujiFilm Imaging System FLA-7000. Micro PET/CT scans of Flortaucipir (18F) were obtained in normal rats to determine if the presence of MAO-A/B inhibitor Pargyline altered tracer retention. Saturation binding Kd is 0.56 ± 0.06 nM in AD brain derived PHF tau. In functional competitive inhibition assays, 67 of 72 tested CNS proteins has <50% inhibition at 10 uM flortaucipir, a concentration at least 5 logs above expected tracer levels in human brain. The IC50 is between 1 and 10 uM for the norepinephrine transporter, polyamine site, acetylcholinesterase, μ-opiate receptor, MAO-B and 0.57 μM for MAO-A. Saturable binding studies in normal brain homogenates from multiple donors and brain regions provided Kd values ranging from 8 to 18 nM. Furthermore, 3 different MAO-A inhibitors displaced Flortaucipir (18F) binding in competitive inhibition assays on the same tissue. In kinetic binding studies, koff for recombinant MAO-A is about 9 times greater than for PHF tau while kon rates are comparable. MAO-A/B inhibitor Pargyline had no effect on Flortaucipir (18F) micro PET-CT imaging of rat brains. Autoradiography confirmed retention of Flortaucipir in neuromelanocytes in substantia nigrabut not in striatum of any age. Flortaucipir binds potently to AD brain derived PHF tau. Taken together, our results indicate that binding of Flortaucipir (18F) to MAO-A is weaker than to PHF tau and are consistent with the absence of clinically important MAO-A binding patterns in human PET imaging. Striatum uptake of Flortaucipir (18F) seen in human PET/CT scans was not seen by ARG on post-mortem brain sections.