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

Abstract

(+)-α-[11C]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 [11C]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 (+)-α- [11C]DTBZ. Dynamic acquisition consisted of a 15-frame sequence over 1 h. Analysis methods included birth creation of pixel-by-pixel functional images of transport (K1) and binding (DV(tot)) 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 K1 and DV(tot), and three compartments, estimating K1-k4. For the more complex configuration, we examined the stability of various binding-related parameters including k3 (k(on)B(max)'), k3/k4 (B(max)'K(d)), D(sp) [K1/k2)(k3/k4)], and DV(tot) [K1/k2(1 + k3/k4)]. 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 DV(tot). Without constraining parameters in the three- compartment model fits, DV(tot) was found to provide a more stable estimate of binding density than either k3, k3/k4, or DV(sp). 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 DV(tot) estimates of 0.997. We conclude that (+)-α-[11C]DTBZ and PET can provide excellent measures of VMAT2 density in the human brain.