title: Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography.
abstract: The in vivo kinetic behavior of [11C]flumazenil ([11C]FMZ), a non-subtype-specific central benzodiazepine antagonist, is characterized using compartmental analysis with the aim of producing an optimized data acquisition protocol and tracer kinetic model configuration for the assessment of [11C]FMZ binding to benzodiazepine receptors (BZRs) in human brain. The approach presented is simple, requiring only a single radioligand injection. Dynamic positron emission tomography data were acquired on 18 normal volunteers using a 60- to 90-min sequence of scans and were analyzed with model configurations that included a three-compartment, four-parameter model, a three-compartment, three-parameter model, with a fixed value for free plus nonspecific binding; and a two-compartment, two-parameter model. Statistical analysis indicated that a four-parameter model did not yield significantly better fits than a three-parameter model. Goodness of fit was improved for three- versus two-parameter configurations in regions with low receptor density, but not in regions with moderate to high receptor density. Thus, a two-compartment, two-parameter configuration was found to adequately describe the kinetic behavior of [11C]FMZ in human brain, with stable estimates of the model parameters obtainable from as little as 20-30 min of data. Pixel-by-pixel analysis yields functional images of transport rate (K1) and ligand distribution volume (DV"), and thus provides independent estimates of ligand delivery and BZR binding.
authors.affiliation: Division of Nuclear Medicine, University of Michigan, Ann Arbor 48109.
authors.forename: R A
authors.initials: RA
authors.lastname: Koeppe
authors.forename: V A
authors.initials: VA
authors.lastname: Holthoff
authors.forename: K A
authors.initials: KA
authors.lastname: Frey
authors.forename: M R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: D E
authors.initials: DE
authors.lastname: Kuhl
mesh_terms: D000328:Adult; D000465:Algorithms; D001812:Blood-Brain Barrier; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D005442:Flumazenil / Q000493:pharmacokinetics*; D006801:Humans; D008024:Ligands; D010539:Permeability; D011963:Receptors, GABA-A / Q000378:metabolism*; D014055:Tomography, Emission-Computed
chemical_list: D002250:Carbon Radioisotopes; D008024:Ligands; D011963:Receptors, GABA-A; D005442:Flumazenil