Kinetic evaluation of [11C]dihydrotetrabenazine by dynamic PET: measurement of vesicular monoamine transporter.
(+)-alpha-[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 (+)-alpha-[11C]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 (K1) 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 K1 and DVtot and three compartments, estimating K1-k4. For the more complex configuration, we examined the stability of various binding-related parameters including k3 (konBmax'), k3/k4 (Bmax'/Kd), DVsp[(K1/k2)(k3/k4)], and DVtot [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 DVtot. Without constraining parameters in the three-compartment model fits, DVtot was found to provide a more stable estimate of binding density than either k3, k3/k4, 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-[11C]DTBZ and PET can provide excellent measures of VMAT2 density in the human brain.
Koeppe
R A
RA
Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
Frey
K A
KA
Vander Borght
T M
TM
Karlamangla
A
A
Jewett
D M
DM
Lee
L C
LC
Kilbourn
M R
MR
Kuhl
D E
DE
D000328:Adult; D001665:Binding Sites; D001692:Biological Transport; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008962:Models, Theoretical; D009479:Neuropeptides; D011869:Radioligand Assay; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014055:Tomography, Emission-Computed; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; C493452:SLC18A2 protein, human; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D013747:Tetrabenazine