Kinetic evaluation of [C-11]dihydrotetrabenazine by dynamic PET: Measurement of vesicular monoamine transporter

(+)-alpha-[C-11]Dihydrotetrabenazine (DTBZ) binds to the vesicular monoamine transporter (VMAT2) located in presynaptic vesicles. The purpose of this work was to evaluate various model configurations for analysis of [C-11]DTBZ with the aim of providing the optimal measure of monoamine vesicular transporter density obtainable from a single dynamic PET study. PET studies on seven young normal volunteer subjects, ages 20-35, were performed following i.v. injection of 666 +/- 37 MBq (18 +/- 1 mCi) of (+)-alpha-[C-11]DTBZ. Dynamic acquisition consisted of a 15-frame sequence over 1 h. Analysis methods included both creation of pixel-by-pixel functional images of transport (K-1) and binding (DVtot) and nonlinear least-squares analysis of volume-of-interest data. Pixel-by-pixel calculations were performed for both two-compartment weighted integral calculations and slope-intercept estimations from Logan plots. Nonlinear least-squares analysis was performed applying model configurations with both two-compartments, estimating K-1 and DVtot, and three compartments, estimating K-1-k(4). For the more complex configuration, we examined the stability of various binding-related parameters including k(3) (k(on)B(max)'), k(3)/k(4) (B-max'/K-d), DVsp [(K-1/k(2))(k(3)/k(4))], and DVtot [K-1/k(2)(1 + k(3)/k(4))]. The three-compartment model provided significantly improved goodness-of-fit compared to the two-compartment model, yet did not increase the uncertainty in the estimate of the DVtot. Without constraining parameters in the three-compartment model fits, DVtot was found to provide a more stable estimate of binding density than either k(3), k(3)/k(4), or DVsp. The two-compartment least-squares analysis yielded approximately 10% underestimations of the total distribution. However, this bias was found to be very consistent from region to region as well as across subjects as indicated by the correlation between two- and three-compartment DVtot estimates of 0.997. We conclude that (+)-alpha-[C-11]DTBZ and PET can provide excellent measures of VMAT2 density in the human brain.