title: Equilibrium versus compartmental analysis for assessment of the vesicular monoamine transporter using (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) and positron emission tomography.
abstract: This work compares equilibrium to kinetic analysis of positron emission tomography data for the assessment of vesicular monoamine transporter (VMAT2) binding density using (+)-alpha-[11C]dihydrotetrabenazine ((+)-alpha-[11C]DTBZ). Studies were performed for 80 minutes after intravenous administration of 18 +/- 1 mCi (+)-alpha-[11C]DTBZ on 9 young control subjects, 20 to 45 years of age. A 9-mCi bolus was injected over the first minute of the study, whereas the remaining 9 mCi were infused at a constant rate over the following 79 minutes. Steady-state was reached in both blood and brain by approximately 30 minutes after initiation of the study. Nonlinear least-squares analysis using two- and three-compartment models, weighted integral analysis using a two-compartment configuration, and Logan plot analysis all yielded kinetic estimates of the total tissue distribution volume, DVtot(kin). These results were compared with equilibrium distribution volume estimates, DVtot(eq), calculated from the tissue to metabolite corrected arterial plasma concentration ratio after 30 minutes. Kinetic modeling results from this study were in close agreement with prior bolus-injection (+)-alpha-[11C]DTBZ studies. In the current study, coefficients of variation in DVtot(kin) (19% to 23% across regions) and DVtot(eq) (18% to 22%) were nearly identical. Equilibrium estimates of DVtot were slightly lower than kinetic estimates, averaging 5% +/- 9% lower (P = 0.04, paired t test) in regions of high binding density (caudate and putamen), but only 2% +/- 6% (P = 0.09) in lower binding density regions (cortex, thalamus, cerebellum). DVtot(eq) estimates, however, still correlated highly with DVtot(kin) estimates (r = 0.977-0.989). Steady-state conditions can be achieved in both tissue and blood by 30 minutes, and the tissue-to-blood ratios of (+)-alpha-[11C]DTBZ at equilibrium yield DVtot(eq) measures that are in close agreement with DVtot(kin) estimates. Thus, a simple, easily tolerated protocol using a loading bolus followed by continuous infusion can provide excellent measures of VMAT2 binding.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Koeppe
authors.forename: K A
authors.initials: KA
authors.lastname: Frey
authors.forename: A
authors.initials: A
authors.lastname: Kume
authors.forename: R
authors.initials: R
authors.lastname: Albin
authors.forename: M R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: D E
authors.initials: DE
authors.lastname: Kuhl
mesh_terms: D000328:Adult; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000378:metabolism; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D013747:Tetrabenazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed / Q000379:methods; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: 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