Graphical analysis and simplified quantification of striatal and extrastriatal dopamine D₂ receptor binding with [¹²³I]epidepride SPECT

The purpose of this study was to extend the graphical analysis of reversible tracer binding to account for labeled lipophilic metabolites (metabolites) in quantifying [¹²³I]epidepride binding to striatal and extrastriatal D₂ receptors and, additionally, to evaluate the feasibility of simplified analysis to measure the specific volume of distribution (V₃') using single-sample blood data because the tissue ratio (R(T)) may be a less reliable measure of D₂ binding in the presence of metabolites. Methods: Multilinear regression analysis (MLRA) and graphical analysis (GA) using plasma parent (P) plus metabolite (M) activities as input and time activities of receptor-free (RF, cerebellum) and receptor-containing regions (RR, striatum and temporal cortex) derived V₃' = (α(RR)/(P) - α(RF)/(P), V₃' = (1 + δ) (α(RR) - α(RF)) and R(T) = V₃'/(V₂/(P)' + δV₂/(M)'), where α is a regression coefficient, δ is the equilibrium area ratio of M and P, and (V₂(P')N₂(M')) are the corresponding nondisplaceable distribution volumes. V₃' by simplified analysis (SA) was calculated from R(T) determined without blood data and (V₂/(P)' + δV₂/(M)') with single-blood sample data. The accuracy of these three V₃' values was assessed relative to the metabolite- accounted kinetic analysis (KA) for [¹²³I]epidepride SPECT studies of 11 healthy volunteers, in which each participant had 27 scans and 30 plasma samples drawn during the 14 h after injection. Results: All three V₃' values (mL/g) significantly correlated with those by KA (r≥ 0.90) (striatum/temporal cortex: MLRA, 77.8 ± 36.6/2.35 ± 1.16; GA, 98.8 ± 34.2/4.61 ± 1.77; SA, 83.9 ± 24.8/4.26 ± 1.74; KA, 107.6 ± 34.4/5.61 ± 1.84). However, the correlation between RT and V₃' was only moderate (r≤ 0.65) because of significant intersubject variability (23%) in (V₂/(P)' + δV₂/(U)'). Conclusion: The graphical analysis can be extended to account for metabolites in measuring D₂ binding with [¹²³I]epidepride SPECT for both high and low D₂ density regions. Additionally, simplified V₃' measurements with single blood sampling are feasible and may be a practical alternative to the tissue ratio RT because R(T) suffers as a measure of D₂ binding from significant intersubject variability in the metabolite- contributed distribution volume of the nondisplaceable compartment.