Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Biochemical Research Methods, Chemistry, Medicinal, Chemistry, Analytical, Biochemistry & Molecular Biology, Pharmacology & Pharmacy, Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3405 Organic chemistry

Abstract:

Objectives: [18F]T808 and [18F]T807 (respectively AVE-680 and AVE-1451), have shown promising results as tracers for in vivo imaging of neurofibrillary tangles (NFTs). Biodistribution, radiometabolite analysis and autoradiography studies were performed with both tracers in order to acquire comparative preclinical data and establish T808 and T807 as benchmark compounds for the evaluation of recently reported tau tracers (PBB3, THK-5105, THK-5117, BF-158, BF-170, lansoprazole and astemizole) and newly synthesized ligands in semi-quantitative autoradiography studies. Methods: [18F]T808 and [18F]T807 were synthesized according to a published procedure [1, 2]. 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 and [18F]T807. Radiometabolites of [18F]T808 and [18F]T807 were quantified in plasma at 2, 10, 30 and 60 min p.i. and in brain at 10 and 60 min p.i. Semi-quantitative autoradiography studies were done with [18F]T808, [18F]T807 and [11C]PIB on human tissue sections of AD-brains and P301L transgenic mice models and their wild-type controls. Slices were incubated with 0.74 MBq/500 µL of tracer with/without 1 µM of cold reference compounds. Results: Biodistribution studies confirmed the reported rapid brain uptake and washout. Analysis of brain homogenate extracts showed the presence of two polar radiometabolites and a fraction of intact tracer of 88% at 10 min and 34% at 60 min p.i. for T808. In plasma, 34% of radioactivity was present as intact tracer at 10 min p.i. and 26% at 60 min p.i. No radiometabolites were detected for [18F]T807 in brain or plasma. In the semi-quantitative autoradiography studies on human AD-slices we observed more than 50% tau-selective blocking of [18F]T808 and [18F]T807 in the presence of 1 µM of reported and newly synthesized ligands. Displacement of [11C]PIB was negligible. No specific binding to murine tau in the P301L transgenic mouse model was observed. Conclusions: This research determined moieties needed for selective interaction with NFTs, furthermore, they provided a straightforward comparison of the currently reported tau tracers. As a result these data could be used to synthesize new highly selective and specific tau-tracers. References: [1] Zhang W et al. J Alzheimers Dis 2012; 31:601-612 [2] Shoup TM et al. J Labelled Comp Radiopharm 2013; 56:736-740