Column-switching HPLC for the analysis of plasma in PET imaging studies

Hilton, John; Yokoi, Fuji; Dannals, Robert F.; Ravert, Hayden T.; Szabó, Zsolt; Wong, Dean F.

doi:10.1016/s0969-8051(00)00125-6

Cited by 193 publications

(185 citation statements)

References 3 publications

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“…[ 11 C]PBR28 parent fraction over the course of the PET scan was determined using the 'Hilton method'. 17 Briefly, urea was added to the plasma samples to give an 8 mol/L concentration to break up plasma-protein binding. The sample was diluted 1:1 with 0.1 mol/L unbuffered Tris and filtered through a 0.45 mm polyvinylidene fluoride syringe filter (Waters Acrodisc LC 13 mm Minispike and 25 mm, Waters, USA) before injection onto the dual HPLC system.…”

Section: Preparation Of [ 11 C]pbr28mentioning

confidence: 99%

Determination of [¹¹C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

Owen

Guo

Kalk

et al. 2014

J Cereb Blood Flow Metab

120

133

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Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BP ND ). Here, we used blockade of the TSPO radioligand [ 11 C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (V ND ), and hence estimate the BP ND . A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [ 11 C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, V ND was estimated via the occupancy plot. Values of BP ND for all subjects were calculated using this V ND estimate. Total volume of distribution (V T ) of MABs (2.94±0.31) was lower than V T of HABs (4.33±0.29) (Po0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50 ¼ 0.34±0.13 mg/kg). The occupancy plot provided a V ND estimate of 1.98 (1.69, 2.26). Based on these V ND estimates, BP ND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [ 11 C]PBR28 V ND and hence BP ND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V ND for TSPO targeting radioligands.

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Section: Preparation Of [ 11 C]pbr28mentioning

confidence: 99%

Determination of [¹¹C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

Owen

Guo

Kalk

et al. 2014

J Cereb Blood Flow Metab

120

133

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“…Before start of a [ 11 C]-MDL or [ 11 C]-DASB PET scan, subject had a venous catheter inserted into one of his arms to administer the radiotracer, and a second venous catheter or radial arterial line was inserted for blood sampling. Radioactivity and radiotracer metabolite concentrations in plasma were measured within the JHU facility using a validated high-performance liquid chromatography (HPLC) method/appropriate radioactive analytical method (Hilton et al 2000). These data were used for construction of a metabolite-corrected plasma input function to calculate specific uptake of the radiotracer in different regions of the brain.…”

Section: Participants and Ethical Approvalmentioning

confidence: 99%

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

et al. 2015

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RationaleCentral modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. ObjectivesThe purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT 2A receptors, dopamine D 2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. MethodsCarbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT 2A receptors, D 2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. ResultsOral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT 2A receptors and low occupancy of striatal D 2 receptors (~12 %). D 2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2 = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D 2 receptors and 33 % of striatal serotonin transporters. ConclusionsThe results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

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“…Plasma metabolite analysis was performed using the column switching HPLC method 21 to determine the parent fraction. In short, plasma samples were treated with urea (8 M) and citric acid (50 mM) and loaded onto the capture column (19 Â 4.6 mm 2 , self-packed with Phenomenex SPE C18 Strata-X sorbent), eluting with 1% acetonitrile in water at a flow rate of 2 mL/min.…”

Section: Input Functionmentioning

confidence: 99%

Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [¹⁸F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans

Sullivan

Lim

Labaree

et al. 2012

J Cereb Blood Flow Metab

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[ 18 F]FPEB is a positron emission tomography tracer which, in preclinical studies, has shown high specificity and selectivity toward the metabotropic glutamate receptor 5 (mGluR5). It possesses the potential to be used in human studies to evaluate mGluR5 function in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome. To define optimal scan methodology, healthy human subjects were scanned for 6 hours following either a bolus injection (n ¼ 5) or bolus-plus-constant-infusion (n ¼ 5) of [ 18 F]FPEB. Arterial blood samples were collected and parent fraction measured by high-performance liquid chromatography (HPLC) to determine the metabolite-corrected plasma input function. Time activity curves were extracted from 13 regions and fitted by various models to estimate V T and BP ND . [ 18 F]FPEB was well fitted by the two-tissue compartment model, MA1 (t* ¼ 30), and MRTM (using cerebellum white matter as a reference). Highest V T values were observed in the anterior cingulate and caudate, and lowest V T values were observed in the cerebellum and pallidum. For kinetic modeling studies, V T and BP ND were estimated from bolus or bolus-plus-constant-infusion scans as short as 90 minutes. Bolus-plus-constant-infusion of [ 18 F]FPEB reduced intersubject variability in V T and allowed equilibrium analysis to be completed with a 30-minute scan, acquired 90-120 minutes after the start of injection.

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Column-switching HPLC for the analysis of plasma in PET imaging studies

Cited by 193 publications

References 3 publications

Determination of [¹¹C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

Determination of [¹¹C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [¹⁸F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans

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Column-switching HPLC for the analysis of plasma in PET imaging studies

Cited by 193 publications

References 3 publications

Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [18F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans

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Product

Resources

About

Determination of [¹¹C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

Determination of [¹¹C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [¹⁸F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans