Quantitative evaluation of 11C-PIB binding in amyloid precursor protein transgenic mouse brains

Introduction 11C-PIB is a widely-used PET ligand to visualize amyloid beta (Abeta) plaques in vivo. Although the nature of its binding properties is yet to be clarified, detailed quantitative PET assays of living animal models may provide critical insights into the molecular basis of the radioligand kinetics. Total volume of distribution (VT) derived from time-activity curves in the plasma (pTAC) and brain (tTAC) is an indicator of the affinity of the ligand for the total binding sites in tissues. In this study, we compared regional VT values among aged wild-type (WT) and amyloid precursor protein (APP) transgenic (Tg) and young WT mice to examine alterations of the ligand kinetics in physiological aging and pathological amyloidogenesis. Furthermore, the applicability of reference tissue models that use only tTACs was assessed as more practical analysis.\nMethods Female aged APP Tg (23-26 mo.; 20-29g; n=4) and WT (25 mo.; 26g; n=1) and male young control (YC) WT (9.7+/-1.8 wk; 24+/-2g; n=6) mice were studied. Simultaneously with the intravenous 11C-PIB (0.4-1.8 mCi) injection, 90-min PET data acquisition and serial arterial blood sampling were started. For the blood samples, radioactivity per unit volume and parent radioligand fraction in the plasma were measured to determine pTAC. Regional brain tTACs were obtained from dynamic PET data with the anatomical assistance of MRI. Regional VT was estimated with compartment model analysis (CMA) and Logan analysis (LA) 1. For the evaluation of the specific 11C-PIB binding to Abata plaques, VT ratio to the cerebellum (DVR) was also calculated using VT obtained with CMA and LA. DVRs were also calculated by simplified reference tissue model (SRTM) 2, and were compared with those with CMA and LA.\nResults and Conclusion The 2-tissue model fitted tTACs in all regions including the cerebellum of Tg and aged WT mice better than did the 1-tissue model, whereas the 1-tissue model resulted in a better fit to the most tTACs of YC mice. Cerebellar VT values of Tg and aged WT mice were higher than those in YC mice. VT values in the neocortex and hippocampus of Tg mice were elevated in consistency with the Abeta deposition. DVRs estimated with SRTM were well correlated with those determined with LA (r2=0.89) and CMA (r2=0.88). The present data support the ability of quantitative PET measurements in mice to distinctly demonstrate changes in non-specific and specific 11C-PIB retentions related to aging and amyloid pathology, respectively. The use of SRTM is also validated as a feasible, non-invasive analysis to quantitatively evaluate the interaction between 11C-PIB and Abata plaques. \n1) Logan J, et al. J Cereb Blood Flow Metab, 1990.2) Lammertsma AA, et al., Neuroimage, 1996.The 8th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM2010