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Background  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 [ 11 C]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).    Methods  In 3P++ analysis for [ 11 C]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.    Results  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 ( r  2  = 0.972 and slope = 0.845) and in one AD ( r  2  = 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 ( r  2  = 0.739 and slope = 0.461). Similar results were shown between 3P++ and 4P analyses:  r  2  = 0.953 for intra-subject  k  3  in NC,  r  2  = 0.907 for that in AD and  r  2  = 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.    Conclusions  In [ 11 C]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.

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