title: Quantification of ligand PET studies using a reference region with a displaceable fraction: application to occupancy studies with [(11)C]-DASB as an example.
abstract: This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BP(D)=DVR-1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BP(D) that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [(11)C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test-retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BP(D) calculated either with plasma or with a reference input and high reproducibility.
authors.affiliation: MRC Clinical Sciences Centre, Hammersmith Hospital, London, UK. federico.turkheimer@imperial.ac.uk
authors.forename: Federico E
authors.initials: FE
authors.lastname: Turkheimer
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Selvaraj
authors.forename: Rainer
authors.initials: R
authors.lastname: Hinz
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Murthy
authors.forename: Zubin
authors.initials: Z
authors.lastname: Bhagwagar
authors.forename: Paul
authors.initials: P
authors.lastname: Grasby
authors.forename: Oliver
authors.initials: O
authors.lastname: Howes
authors.forename: Lula
authors.initials: L
authors.lastname: Rosso
authors.forename: Subrata K
authors.initials: SK
authors.lastname: Bose
mesh_terms: D000328:Adult; D000814:Aniline Compounds / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D002250:Carbon Radioisotopes; D002531:Cerebellum / Q000000981:diagnostic imaging* / Q000378:metabolism; D015283:Citalopram / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D012016:Reference Values; D015203:Reproducibility of Results; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics; D013440:Sulfides / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D015283:Citalopram; D008024:Ligands; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; C412822:3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile