Preclinical evaluation of novel PET-tracers for tau imaging

Objectives We studied the preclinical characteristics of two tau PET-tracer candidates for the in vivo imaging of neurofibrillary tangles (NFTs) in Alzheimer’s disease (AD). Autoradiography (ARX) studies were used to determine binding characteristics in comparison with T807 (AV-1451). Biodistribution and radiometabolite studies were performed in mice to evaluate the pharmacokinetic properties of the tracer candidates.

Methods [¹¹C]TAU7 and [¹¹C]TAU9 were synthesized by a one-step methylation of the precursor with [¹¹C]methyl iodide ([¹¹C]MeI) in DMSO in the presence of Cs₂CO₃. The crude reaction mixture was purified using reverse phase HPLC. Tracers biodistribution was studied in NMRI-mice at 2, 10, 30 and 60 min (n = 3 / time point) post injection (p.i.). Radiometabolites of [¹¹C]TAU9 were quantified in mouse plasma at 2 and 10 min p.i. (n = 3 / time point). Brain radiometabolites of [¹¹C]TAU7 and [¹¹C]TAU9 were determined at 10 min p.i. (n = 3 / time point). In vitro binding to tissue sections of human AD-brains was investigated with ARX.

Results [¹¹C]TAU7 and [¹¹C]TAU9 were obtained with a radiolabeling yield (relative to total recovered carbon-11) of, respectively, 30% and 40%. [¹¹C]TAU7 was collected with a specific activity of 36 - 128 GBq/µmol at the end of synthesis (EOS, n = 3) and [¹¹C]TAU9 was obtained with a specific activity of 15 - 93 GBq/µmol at EOS (n = 5). Biodistribution studies showed rapid and high brain uptake (3.5 %ID and 1.7 %ID at 2 min p.i. for, respectively, [¹¹C]TAU7 and [¹¹C]TAU9), but slow wash-out. Analysis of brain homogenate extracts of [¹¹C]TAU9 indicates fast metabolism (probably ester hydrolysis) in brain, with a fraction of intact tracer of 3% at 10 min p.i. In plasma, 97% of [¹¹C]TAU9’ radioactivity was present as polar metabolite at 10 min p.i For [¹¹C]TAU7 on the other hand, no radiometabolites were detected at 10 min p.i. in mouse brain.. In vitro ARX on human tissue sections of AD-brains showed binding to tau-rich regions that was highly displaceable (> 69%) in the presence of 1 µM of T807 or authentic reference compound.

Conclusions [¹¹C]TAU7 and [¹¹C]TAU9 have a high initial brain uptake, but slow wash-out in mice. Rapid metabolism was seen in mouse plasma and brain for [¹¹C]TAU9. No radiometabolites were detected for [¹¹C]TAU7 in mouse brain. $$graphic_BD5D23C4-F0EB-402C-A3B4-A7ED0B29ED31$$