Volume-of-interest-based supervised cluster analysis for pseudo-reference region selection in [(18)F]DPA-714 PET imaging of the rat brain

METHOD: Aim of this study was to automatically select a suitable pseudo-reference brain region for the accurate, non-invasive quantification of neuroinflammation in a rat brain using dynamic [(18)F]DPA-714 PET imaging. PROCEDURES: A supervised clustering analysis approach considering three kinetic classes (SVCA3) was used to select an appropriate pseudo-reference brain region. This pseudo-reference region was determined by selecting only brain regions with low specific tracer uptake (SVCA3(low)) or by taking into account all brain regions and weighting each brain region with the corresponding fraction of low specific binding (SVCA3(wlow)). Both SVCA3 approaches were evaluated in an animal model of neuro-inflammation induced by lipopolysaccharide injection in the right striatum of female Wistar rats. For this study setup, a population of 25 female Wistar rats received a dynamic PET scan after injection of ~ 60 MBq [(18)F]DPA-714. Animals were scanned at baseline (n = 3) and at different time points after inducing neuroinflammation: 1 day (n = 3), 3 days (n = 12), 7 days (n = 4), and 30 days (n = 3). Binding potential (BP) values using a simplified reference tissue model (SRTM) and the contralateral striatum as pseudo-reference region were considered as a reference method (BP(L STR)) and compared with SRTM BP values using a pseudo-reference region obtained by either the SVCA3(low) or SVCA3(wlow) approach for both a 90- and 120-min acquisition time interval. RESULTS: For the right striatum, SRTM BP values using a SVCA3(low)- or SVCA3(wlow)-based pseudo-reference region demonstrated a strong and highly significant correlation with SRTM BP(L STR) values (Spearman r ≥ 0.89, p < 0.001). For the SVCA3(low) approach, Friedman tests revealed no significant difference with SRTM BP(L STR) values for a 120-min acquisition time while small but signification differences were found for a 90-min acquisition time (p < 0.05). For the SVCA3(wlow) approach, highly signification differences (p < 0.001) were found with SRTM BP(L STR) values for both a 90- and 120-min acquisition time interval. CONCLUSIONS: A SVCA3 approach using three kinetic classes allowed the automatic selection of pseudo-reference brain regions with low specific tracer binding for accurate and non-invasive quantification of rat brain PET imaging using [(18)F]DPA-714. A shorter acquisition time interval of 90 min can be considered with only limited impact on the SVCA3-based selection of the pseudo-reference brain regions.