Evaluation of the Feasibility of Screening Tau Radiotracers Using an Amyloid Biomathematical Screening Methodology.

The purpose of this study is to evaluate the feasibility of extending a previously developed amyloid biomathematical screening methodology to support the screening of tau radiotracers during compound development. 22 tau-related PET radiotracers were investigated. For each radiotracer, in silico MLogP, V x , and in vitro K D were input into the model to predict the in vivo K 1 , k 2 , and BPND under healthy control (HC), mild cognitive impaired (MCI), and Alzheimer's disease (AD) conditions. These kinetic parameters were used to simulate the time activity curves (TACs) in the target regions of HC, MCI, and AD and a reference region. Standardized uptake value ratios (SUVR) were determined from the integrated area under the TACs of the target region over the reference region within a default time window of 90-110 min. The predicted K 1 , k 2 , and BPND values were compared with the clinically observed values. The TACs and SUVR distributions were also simulated with population variations and noise. Finally, the clinical usefulness index (CUI) ranking was compared with clinical comparison results. The TACs and SUVR distributions differed for tau radiotracers with lower tau selectivity. The CUI values ranged from 0.0 to 16.2, with 6 out of 9 clinically applied tau radiotracers having CUI values higher than the recommend CUI value of 3.0. The differences between the clinically observed TACs and SUVR results showed that the evaluation of the clinical usefulness of tau radiotracer based on single target binding could not fully reflect in vivo tau binding. The screening methodology requires further study to improve the accuracy of screening tau radiotracers. However, the higher CUI rankings of clinically applied tau radiotracers with higher signal-to-noise ratio supported the use of the screening methodology in radiotracer development by allowing comparison of candidate radiotracers with clinically applied radiotracers based on SUVR, with respect to binding to a single target.