Selectivity requirements for diagnostic imaging of neurofibrillary lesions in Alzheimer's disease: a simulation study

Neuroimage. 2012 Apr 15;60(3):1724-33. doi: 10.1016/j.neuroimage.2012.01.066. Epub 2012 Jan 16.


Whole-brain imaging is a promising strategy for premortem detection of tau-bearing neurofibrillary lesions that accumulate in Alzheimer's disease. However, the approach is complicated by the high concentrations of potentially confounding binding sites presented by beta-amyloid plaques. To predict the contributions of relative binding affinity and binding site density to the imaging-dynamics and selectivity of a hypothetical tau-directed radiotracer, a nonlinear, four-tissue compartment pharmacokinetic model of diffusion-mediated radiotracer uptake and distribution was developed. Initial estimates of nonspecific binding and brain uptake parameters were made by fitting data from a previously published kinetic study of Pittsburgh Compound B, an established amyloid-directed radiotracer. The resulting estimates were then used to guide simulations of tau binding selectivity while assuming early-stage accumulation of disease pathology. The simulations suggest that for tau aggregates to represent at least 80% of specific binding signal, binding affinity or density selectivities for tau over beta-amyloid should be at least 20- or 50-fold, respectively. The simulations also suggest, however, that overcoming nonspecific binding will be an additional challenge for tau-directed radiotracers owing to low concentrations of available binding sites. Overall, nonlinear modeling can provide insight into the performance characteristics needed for tau-directed radiotracers in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / metabolism*
  • Aniline Compounds
  • Benzothiazoles / pharmacokinetics*
  • Computer Simulation
  • Humans
  • Image Interpretation, Computer-Assisted / methods
  • Male
  • Models, Neurological
  • Neurofibrillary Tangles / diagnostic imaging*
  • Neurofibrillary Tangles / metabolism*
  • Positron-Emission Tomography / methods*
  • Radiopharmaceuticals / pharmacokinetics
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Thiazoles


  • 2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
  • Aniline Compounds
  • Benzothiazoles
  • Radiopharmaceuticals
  • Thiazoles