Reference Region Modeling Approaches for Amphetamine Challenge Studies with [11C]FLB 457 and PET

Detecting fluctuations in synaptic dopamine levels in extrastriatal brain regions with [11C]FLB 457 and positron emission tomography (PET) is a valuable tool for studying dopaminergic dysfunction in psychiatric disorders. The evaluation of reference region modeling approaches would eliminate the need to obtain arterial input function data. Our goal was to explore the use of reference region models to estimate amphetamine-induced changes in [11C]FLB 457 dopamine D2/D3 binding. Six healthy tobacco smokers were imaged with [11C]FLB 457 at baseline and at 3 hours after amphetamine (0.4 to 0.5 mg/kg, per os) administration. Simplified reference tissue models, SRTM and SRTM2, were evaluated against the 2-tissue compartmental model (2TC) to estimate [11C]FLB 457 binding in extrastriatal regions of interest (ROIs), using the cerebellum as a reference region. No changes in distribution volume were observed in the cerebellum between scan conditions. SRTM and SRTM2 underestimated binding, compared with 2TC, in ROIs by 26% and 9%, respectively, with consistent bias between the baseline and postamphetamine scans. Postamphetamine, [11C]FLB 457 binding significantly decreased across several brain regions as measured with SRTM and SRTM2; no significant change was detected with 2TC. These data support the sensitivity of [11C]FLB 457 for measuring amphetamine-induced dopamine release in extrastriatal regions with SRTM and SRTM2.

Download Full-text

Evaluation of Simplified Kinetic Analyses for Measurement of Brain Acetylcholinesterase Activity Using N-[11C]Methylpiperidin-4-yl Propionate and Positron Emission Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000117689.98763.6a ◽

2004 ◽

Vol 24 (6) ◽

pp. 600-611 ◽

Cited By ~ 10

Author(s):

Koichi Sato ◽

Kiyoshi Fukushi ◽

Hitoshi Shinotoh ◽

Shinichiro Nagatsuka ◽

Noriko Tanaka ◽

...

Keyword(s):

Ache Activity ◽

Arterial Input Function ◽

Acetylcholinesterase Activity ◽

Input Function ◽

Previous Method ◽

Target Tissue ◽

Standard Analysis ◽

Reference Tissue ◽

Arterial Blood ◽

Positron Emission

The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvist's equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.

Download Full-text

Kinetic Modeling of the Serotonin 5-HT1B Receptor Radioligand [11C]P943 in Humans

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.195 ◽

2009 ◽

Vol 30 (1) ◽

pp. 196-210 ◽

Cited By ~ 44

Author(s):

Jean-Dominique Gallezot ◽

Nabeel Nabulsi ◽

Alexander Neumeister ◽

Beata Planeta-Wilson ◽

Wendol A Williams ◽

...

Keyword(s):

Positron Emission Tomography ◽

Arterial Input Function ◽

Human Subjects ◽

Emission Tomography ◽

Binding Potential ◽

Noninvasive Methods ◽

Reference Tissue ◽

Positron Emission ◽

Tissue Models

[11C]P943 is a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT1B) receptors with positron emission tomography (PET). The purpose of this study was to evaluate [11C]P943 for this application in humans, and to determine the most suitable quantification method. Positron emission tomography data and arterial input function measurements were acquired in a cohort of 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BPND binding potential estimates were computed. [11C]P943 BPND estimates were significantly correlated with in vitro measurements of the density of 5-HT1B receptors, with highest values in the occipital cortex and pallidum. To evaluate noninvasive methods, two- and three-parameter graphical analyses, Simplified Reference Tissue Models (SRTM and SRTM2), and Multilinear Reference Tissue Models (MRTM and MRTM2) were tested. The MRTM2 model provided the best correlation with MA1 binding-potential estimates. Parametric images of the volume of distribution or binding potential of [11C]P943 could be computed using both MA1 and MRTM2. The results show that [11C]P943 provides quantitative measurements of 5-HT1B binding potential.

Download Full-text

Initial Cerebral HM-PAO Distribution Compared to LCBF: Use of a Model Which Considers Cerebral HM-PAO Trapping Kinetics

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1988.30 ◽

1988 ◽

Vol 8 (1_suppl) ◽

pp. S31-S37 ◽

Cited By ~ 11

Author(s):

James L. Lear

Keyword(s):

Arterial Input Function ◽

Input Function ◽

Brain Regions ◽

Male Rats ◽

Type Model ◽

Emission Computed Tomography ◽

Intravenous Injections ◽

Positron Emission ◽

Uptake Pattern ◽

The Brain

The cerebral uptake of [99mTc]– d,l-hexamethylpropyleneamine oxime complex (HM-PAO) was compared to LCBF determined simultaneously with [14C]iodoantipyrine (IAP) using double radionuclide quantitative digital autoradiography. Awake male rats were given intravenous injections of a mixture of 50 μCi IAP and 15 mCi of HM-PAO and killed 20 s after tracer activity had first reached the brain. Two separate autoradiograms were produced from each 20 μm brain section. The autoradiograms were digitized, corrected for cross-contamination, and then converted into images of individual tracer concentration. The diffusible tracer model was used to convert the IAP concentration images into LCBF images. Regional HM-PAO concentration was found not to be linearly related to LCBF as determined with the IAP, and therefore a simple microsphere type model was inadequate in relating HM-PAO uptake to LCBF. A better HM-PAO uptake–LCBF correlation was obtained when the HM-PAO arterial input function was corrected for very rapidly produced, non-cerebrally extracted, metabolites and a kinetic model was used that considered the rate of intracerebral metabolism of HM-PAO to a retained metabolite. Even using this model, however, some differences between HM-PAO uptake and LCBF occurred in certain brain regions. Because these differences were small and the HM-PAO uptake pattern has been shown to be constant for many minutes, HM-PAO can probably be used to estimate LCBF in patients with single positron emission computed tomography (SPECT) imaging.

Download Full-text

Automated Reference Region Extraction and Population-Based Input Function for Brain [11C]TMSX PET Image Analyses

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.194 ◽

2014 ◽

Vol 35 (1) ◽

pp. 157-165 ◽

Cited By ~ 20

Author(s):

Eero Rissanen ◽

Jouni Tuisku ◽

Pauliina Luoto ◽

Eveliina Arponen ◽

Jarkko Johansson ◽

...

Keyword(s):

Arterial Input Function ◽

Input Function ◽

Population Based ◽

Reference Region ◽

Automated Method ◽

Arterial Blood ◽

Positron Emission ◽

Using Data ◽

Multiple Sclerosis Patients ◽

Image Analyses

[11C]TMSX ([7- N-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) is a selective adenosine A2A receptor (A2AR) radioligand. In the central nervous system (CNS), A2AR are linked to dopamine D2 receptor function in striatum, but they are also important modulators of inflammation. The golden standard for kinetic modeling of brain [11C]TMSX positron emission tomography (PET) is to obtain arterial input function via arterial blood sampling. However, this method is laborious, prone to errors and unpleasant for study subjects. The aim of this work was to evaluate alternative input function acquisition methods for brain [11C]TMSX PET imaging. First, a noninvasive, automated method for the extraction of gray matter reference region using supervised clustering (SCgm) was developed. Second, a method for obtaining a population-based arterial input function (PBIF) was implemented. These methods were created using data from 28 study subjects (7 healthy controls, 12 multiple sclerosis patients, and 9 patients with Parkinson's disease). The results with PBIF correlated well with original plasma input, and the SCgm yielded similar results compared with cerebellum as a reference region. The clustering method for extracting reference region and the population-based approach for acquiring input for dynamic [11C]TMSX brain PET image analyses appear to be feasible and robust methods, that can be applied in patients with CNS pathology.

Download Full-text

Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.108 ◽

2011 ◽

Vol 32 (1) ◽

pp. 70-80 ◽

Cited By ~ 21

Author(s):

Federico E Turkheimer ◽

Sudhakar Selvaraj ◽

Rainer Hinz ◽

Venkatesha Murthy ◽

Zubin Bhagwagar ◽

...

Keyword(s):

Specific Binding ◽

Normal Subjects ◽

Volume Of Distribution ◽

Binding Potential ◽

Accurate Estimation ◽

Data Sets ◽

Reference Region ◽

Reference Tissue ◽

Positron Emission ◽

Definition Of

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 BPD = 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 BPD 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. [11C]-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 BPD calculated either with plasma or with a reference input and high reproducibility.

Download Full-text

Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

10.1101/2020.10.29.354696 ◽

2020 ◽

Author(s):

Naoyuki Obokata ◽

Chie Seki ◽

Takeshi Hirata ◽

Jun Maeda ◽

Hideki Ishii ◽

...

Keyword(s):

Arterial Input Function ◽

Inflammatory Diseases ◽

Input Function ◽

Binding Potential ◽

Dependent Manner ◽

Reference Tissue ◽

Molar Activity ◽

The Brain

AbstractPurposePhosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in-vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.Methods[11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in-vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND.Results[11C]MTP38 was synthesized with radiochemical purity ≥ 99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In-vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function.ConclusionWe have provided the first successful preclinical demonstration of in-vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

Download Full-text

The use of a reference tissue arterial input function with low-temporal-resolution DCE-MRI data

Physics in Medicine and Biology ◽

10.1088/0031-9155/55/16/016 ◽

2010 ◽

Vol 55 (16) ◽

pp. 4871-4883 ◽

Cited By ~ 18

Author(s):

M Heisen ◽

X Fan ◽

J Buurman ◽

N A W van Riel ◽

G S Karczmar ◽

...

Keyword(s):

Temporal Resolution ◽

Arterial Input Function ◽

Input Function ◽

Reference Tissue ◽

Dce Mri

Download Full-text

Multiple reference tissue method for contrast agent arterial input function estimation

Magnetic Resonance in Medicine ◽

10.1002/mrm.21311 ◽

2007 ◽

Vol 58 (6) ◽

pp. 1266-1275 ◽

Cited By ~ 55

Author(s):

Cheng Yang ◽

Gregory S. Karczmar ◽

Milica Medved ◽

Walter M. Stadler

Keyword(s):

Contrast Agent ◽

Arterial Input Function ◽

Input Function ◽

Function Estimation ◽

Reference Tissue ◽

Multiple Reference

Download Full-text

Arterial Input Function Derived from Pairwise Correlations Between PET-image Voxels

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.47 ◽

2013 ◽

Vol 33 (7) ◽

pp. 1058-1065 ◽

Cited By ~ 12

Author(s):

Martin Schain ◽

Simon Benjaminsson ◽

Katarina Varnäs ◽

Anton Forsberg ◽

Christer Halldin ◽

...

Keyword(s):

Arterial Input Function ◽

Pearson Correlation ◽

Invasive Procedure ◽

Compartmental Analysis ◽

Input Function ◽

Time Activity ◽

Pairwise Correlation ◽

Positron Emission ◽

Using Data ◽

Suitable Reference

A metabolite corrected arterial input function is a prerequisite for quantification of positron emission tomography (PET) data by compartmental analysis. This quantitative approach is also necessary for radioligands without suitable reference regions in brain. The measurement is laborious and requires cannulation of a peripheral artery, a procedure that can be associated with patient discomfort and potential adverse events. A non invasive procedure for obtaining the arterial input function is thus preferable. In this study, we present a novel method to obtain image-derived input functions (IDIFs). The method is based on calculation of the Pearson correlation coefficient between the time-activity curves of voxel pairs in the PET image to localize voxels displaying blood-like behavior. The method was evaluated using data obtained in human studies with the radioligands [ 11 C]flumazenil and [ 11 C]AZ10419369, and its performance was compared with three previously published methods. The distribution volumes ( VT) obtained using IDIFs were compared with those obtained using traditional arterial measurements. Overall, the agreement in VT was good (~3% difference) for input functions obtained using the pairwise correlation approach. This approach performed similarly or even better than the other methods, and could be considered in applied clinical studies. Applications to other radioligands are needed for further verification.

Download Full-text

Linearized Reference Tissue Parametric Imaging Methods: Application to [11C]DASB Positron Emission Tomography Studies of the Serotonin Transporter in Human Brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000085441.37552.ca ◽

2003 ◽

Vol 23 (9) ◽

pp. 1096-1112 ◽

Cited By ~ 403

Author(s):

Masanori Ichise ◽

Jeih-San Liow ◽

Jian-Qiang Lu ◽

Akihiro Takano ◽

Kendra Model ◽

...

Keyword(s):

Positron Emission Tomography ◽

Human Brain ◽

Positron Emission Tomography Imaging ◽

Emission Tomography ◽

Binding Potential ◽

Parametric Imaging ◽

Reference Tissue ◽

Parametric Images ◽

Positron Emission ◽

Tissue Models

The authors developed and applied two new linearized reference tissue models for parametric images of binding potential ( BP) and relative delivery ( R1) for [11C]DASB positron emission tomography imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTMO) was modified (MRTM) and used to estimate a clearance rate ( k′2) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k′2. The resulting BP and R1 estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual [11C]DASB data. MRTM gave k′2 estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and 1TKA, reducing BP bias markedly over MRTMO from 12–70% to 1–4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R1 bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human [11C]DASB positron emission tomography studies.

Download Full-text