Simplified reference region model for the kinetic analysis of [Tc-99m]TRODAT-1 binding to dopamine transporters in nonhuman primates using single-photon emission tomography

Accurate quantification of neuroreceptors requires full kinetic modeling of the dynamic single-photon emission tomography (SPET) or positron emission tomography (PET) images, with highly invasive arterial blood sampling. This study investigated the application of a reference region kinetic model to the dynamics of [Tc-99m]TRODAT-1 in nonhuman primates, obviating the need f or blood sampling. A series of dynamic SPET scans were performed on two bab oons following the injection of approximately 700 MBq of [Tc-99m]TRODAT-1. Rapid arterial blood samples were taken automatically during scanning. Reco nstructed SPET images were coregistered with magnetic resonance imaging (MR I) scans of the baboons, and regions of interest (ROIs) placed on the stria tum, cerebellum and cerebral hemispheres. The ROI data were combined with m etabolite-corrected blood data, and fitted to a three-compartment kinetic m odel using nonlinear least squares techniques. The same data were also used in a simplified reference region model, in which the input function was de rived from the nondisplaceable tissue compartment. In addition, semiquantit ative blinded analysis was performed by three raters to determine the point of transient equilibrium in the specific binding curves. All methods gener ated values for the ratio of the kinetic rate constants k(3)/k(4), which gi ves an estimate of the binding potential, BP. These were compared with the full kinetic model. The mean values of k(3)/k(4), for the three different a nalysis techniques for each baboon were: 1.17+/-0.21 and 1.12+/-0.13 (full kinetic model), 0.93+/-0.13 and 0.90+/-0.07 (reference region model), and 0 .97+/-0.18 and 0.92+/-0.08 (equilibrium method). The reference region metho d gave significantly lower results than the full kinetic model (P = 0.01), but it also produced a much smaller spread and better quality fits to the k inetic data. The reference region model results for k(3)/k(4) correlated ve ry strongly with the full kinetic analysis (r(2) = 0.992, P<0.001), and wit h the equilibrium model (r(2) = 0.88, P = 0.002), The subjectivity inherent in the equilibrium method produces inferior results compared with both kin etic analyses. It is suggested that the self-consistency of the reference r egion model, which requires no arterial blood sampling, provides a more pre cise and reliable estimate of the binding of [Tc-99m]TRODAT-1 to dopamine t ransporters than full kinetic modeling. The reference region method is also better suited to a routine clinical environment, and would be able to dist inguish smaller differences in dopaminergic function between patient groups .