Noninvasive k₃ estimation method for slow dissociation PET ligands: application to [¹¹C]Pittsburgh compound B

Recently, we reported an information density theory and an analysis of three-parameter plus shorter scan than conventional method (3P+) for the amyloid-binding ligand [¹¹C]Pittsburgh compound B (PIB) as an example of a non-highly reversible positron emission tomography (PET) ligand. This article describes an extension of 3P + analysis to noninvasive ‘3P++’ analysis (3P + plus use of a reference tissue for input function).

In 3P++ analysis for [¹¹C]PIB, the cerebellum was used as a reference tissue (negligible specific binding). Fifteen healthy subjects (NC) and fifteen Alzheimer's disease (AD) patients participated. The k ₃ (index of receptor density) values were estimated with 40-min PET data and three-parameter reference tissue model and were compared with that in 40-min 3P + analysis as well as standard 90-min four-parameter (4P) analysis with arterial input function. Simulation studies were performed to explain k ₃ biases observed in 3P++ analysis.

Good model fits of 40-min PET data were observed in both reference and target regions-of-interest (ROIs). High linear intra-subject (inter-15 ROI) correlations of k ₃ between 3P++ (Y-axis) and 3P + (X-axis) analyses were shown in one NC (r² = 0.972 and slope = 0.845) and in one AD (r² = 0.982, slope = 0.655), whereas inter-subject k ₃ correlations in a target region (left lateral temporal cortex) from 30 subjects (15 NC + 15 AD) were somewhat lower (r² = 0.739 and slope = 0.461). Similar results were shown between 3P++ and 4P analyses: r² = 0.953 for intra-subject k ₃ in NC, r² = 0.907 for that in AD and r² = 0.711 for inter-30 subject k ₃. Simulation studies showed that such lower inter-subject k ₃ correlations and significant negative k ₃ biases were not due to unstableness of 3P++ analysis but rather to inter-subject variation of both k ₂ (index of brain-to-blood transport) and k ₃ (not completely negligible) in the reference region.

In [¹¹C]PIB, the applicability of 3P++ analysis may be restricted to intra-subject comparison such as follow-up studies. The 3P++ method itself is thought to be robust and may be more applicable to other non-highly reversible PET ligands with ideal reference tissue.