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Abstract:

Objectives: We evaluated two reported high affinity and high specificity NFT-tracers [18F]T808 and [18F]T807. Characteristics making these molecules valuable bench mark compounds for development of other NFT-tracers. We studied preclinical characteristics of [18F]T808, and explored whether T807 and other reported NFT-tracers (PIB, FDDNP, BF-158, BF-170, lansoprazole and astemizole) share the same binding site on this protein. We further performed autoradiography experiments on brain sections of a P301L mouse model of AD. Methods: [18F]T808 was synthesized according to a published procedure [1]. We performed a biodistribution study in NMRI-mice at 2, 10, 30 and 60 min (n=4/time point) post injection (p.i.) of [18F]T808. Radiometabolites of [18F]T808 were quantified in plasma and brain at 10 and 60 min p.i. Autoradiography studies were done with [18F]T808 and [18F]T807 on human tissue sections of AD-brains and P301L transgenic mice models and their wild-type controls. Slices were incubated with 0.74 MBq/500µL of tracer with/without 1 µM of cold reference compounds. Results: Biodistribution studies confirmed the reported rapid brain uptake and washout (4.91%ID/g at 2 min and 0.80%ID/g at 30 min p.i.). Analysis of brain homogenate extracts showed the presence of two polar radiometabolites and a fraction of intact tracer of 87% at 10 min and 34% at 60 min p.i. In plasma, 34% of radioactivity was present as intact tracer at 10 min p.i. and 26% at 60 min p.i. Autoradiography on human tissue sections of AD-brains showed binding to tau-rich regions that was up to 75% displaceable in the presence of 1 µM of T808 and/or T807. Binding inhibition with 21% was observed for PIB, 23% for BF-158 and 31% for BF-170. Lansoprazole, astemizole and FDDNP did not show significant displacement. No specific binding to murine tau in the P301L transgenic mouse model was observed. Conclusions: Results display the usefulness of T808 and T807 as bench mark compounds for the in vitro evaluation of new PET imaging agents for tauopathies. [18F]T808 does not look suitable to quantify NFTs in brain of P301L transgenic mice. References: [1] Zhang W et al. J.Alzheimers.Dis 2012; 31:601-612