KINETIC EVALUATION OF [C-11] DIHYDROTETRABENAZINE BY DYNAMIC PET - MEASUREMENT OF VESICULAR MONOAMINE TRANSPORTER

(+)-alpha-[C-11]Dihydrotetrabenazine (DTBZ) binds to the vesicular mon oamine transporter (VMAT2) located in presynaptic vesicles. The purpos e of this work was to evaluate various model configurations for analys is of [C-11]DTBZ with the aim of providing the optimal measure of mono amine vesicular transporter density obtainable from a single dynamic P ET study. PET studies on seven young normal volunteer subjects, ages 2 0-35, were performed following i.v. injection of 666 +/- 37 MBq (18 +/ - 1 mCi) of (+)-alpha-[C-11]DTBZ. Dynamic acquisition consisted of a 1 5-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. Pix el-by-pixel calculations were performed for both two-compartment weigh ted integral calculations and slope-intercept estimations from Logan p lots. Nonlinear least-squares analysis was performed applying model co nfigurations with both two-compartments, estimating K-1 and DVtot, and three compartments, estimating K-1-k(4). For the more complex configu ration, we examined the stability of various binding-related parameter s 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-compar tment model provided significantly improved goodness-of-fit compared t o the two-compartment model, yet did not increase the uncertainty in t he estimate of the DVtot. Without constraining parameters in the three -compartment model fits, DVtot was found to provide a more stable esti mate of binding density than either k(3), k(3)/k(4), or DVsp. The two- compartment least-squares analysis yielded approximately 10% underesti mations of the total distribution. However, this bias was found to be very consistent from region to region as well as across subjects as in dicated by the correlation between two- and three-compartment DVtot es timates of 0.997. We conclude that (+)-alpha-[C-11]DTBZ and PET can pr ovide excellent measures of VMAT2 density in the human brain.