title: Simple and rapid quantification of serotonin transporter binding using [11C]DASB bolus plus constant infusion.
abstract: In-vivo quantification of serotonin transporters (SERT) in human brain has been a mainstay of molecular imaging in the field of neuropsychiatric disorders and helped to explore the underpinnings of several medical conditions, therapeutic and environmental influences. The emergence of PET/MR hybrid systems and the heterogeneity of SERT binding call for the development of efficient methods making the investigation of larger or vulnerable populations with limited scanner time and simultaneous changes in molecular and functional measures possible. We propose [11C]DASB bolus plus constant infusion for these applications and validate it against standard analyses of dynamic PET data.
  
  
  
  [11C]DASB bolus/infusion optimization was performed on data acquired after [11C]DASB bolus in 8 healthy subjects. Subsequently, 16 subjects underwent one scan using [11C]DASB bolus plus constant infusion with Kbol160-179min and one scan after [11C]DASB bolus for inter-method reliability analysis. Arterial blood sampling and metabolite analysis were performed for all scans. Distribution volumes (VT) were obtained using Logan plots for bolus scans and ratios between tissue and plasma parent activity for bolus plus infusion scans for different time spans of the scan (VT-70for 60-70min after start of tracer infusion, VT-90for 75-90min, VT-120for 100-120min) in 9 subjects. Omitting blood data, binding potentials (BPND) obtained using multilinear reference tissue modeling (MRTM2) and cerebellar gray matter as reference region were compared in 11 subjects.
  
  
  
  A Kbolof 160min was observed to be optimal for rapid equilibration in thalamus and striatum. VT-70showed good intraclass correlation coefficients (ICCs) of 0.61-0.70 for thalamus, striatal regions and olfactory cortex with bias ≤5.1% compared to bolus scans. ICCs increased to 0.72-0.78 for VT-90and 0.77-0.93 for VT-120in these regions. BPND-90had negligible bias ≤2.5%, low variability ≤7.9% and ICCs of 0.74-0.87; BPND-120had ICCs of 0.73-0.90. Low-binding cortical regions and cerebellar gray matter showed a positive bias of ~8% and ICCs 0.57-0.68 at VT-90. Cortical BPNDsuffered from high variability and bias, best results were obtained for olfactory cortex and anterior cingulate cortex with ICC=0.74-0.75 for BPND-90. High-density regions amygdala and midbrain had a negative bias of -5.5% and -22.5% at VT-90with ICC 0.70 and 0.63, respectively.
  
  
  
  We have optimized the equilibrium method with [11C]DASB bolus plus constant infusion and demonstrated good inter-method reliability with accepted standard methods and for SERT quantification using both VTand BPNDin a range of different brain regions. With as little as 10-15min of scanning valid estimates of SERT VTand BPNDin thalamus, amygdala, striatal and high-binding cortical regions could be obtained. Blood sampling seems vital for valid quantification of SERT in low-binding cortical regions. These methods allow the investigation of up to three subjects with a single radiosynthesis.
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Gryglewski
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Rischka
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Hahn
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors.forename: G M
authors.initials: GM
authors.lastname: James
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Klebermass
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Hienert
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Silberbauer
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Vanicek
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Kautzky
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Berroterán-Infante
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Nics
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Traub-Weidinger
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Applied Diagnostics, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Mitterhauser
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria; Center for Biomarker Research in Medicine (CBmed), Graz, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Wadsak
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Hacker
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria. Electronic address: rupert.lanzenberger@meduniwien.ac.at.
authors.forename: R
authors.initials: R
authors.lastname: Lanzenberger
mesh_terms: D000328:Adult; D001596:Benzylamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000032:analysis*; D014018:Tissue Distribution
chemical_list: D001596:Benzylamines; D002250:Carbon Radioisotopes; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins
keywords: Binding potential; Bolus plus constant infusion; Distribution volume; PET; Serotonin transporter; [(11)C]DASB