
Vincent J Cunningham- M.A.,D.Phil.
- University of Aberdeen
Vincent J Cunningham
- M.A.,D.Phil.
- University of Aberdeen
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226
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Introduction
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Current institution
Publications
Publications (226)
Dissolution dynamic nuclear polarisation (dDNP) of 13C‐labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of...
The rate of blood flow through a tissue (F) is a critical parameter for assessing the functional efficiency of a blood vessel network following angiogenesis. This chapter aims to provide the principles behind the estimation of F, how F relates to other commonly used measures of tissue perfusion, and a practical approach for estimating F in laborato...
Results:
Kinetic analysis of (11)C-GSK215083 uptake in human brain demonstrated the multilinear model, MA2, to represent the method of choice when a blood input was available and the full tissue reference method when no input was available. Pharmacological dissection of the in vivo (11)C-GSK215083 specific binding showed the ligand bound mostly th...
Background:
The ability to quantify the capacity of a central nervous system (CNS) drug to cross the human blood-brain barrier (BBB) provides valuable information for de-risking drug development of new molecules. Here, we present a study, where a suitable positron emission tomography (PET) ligand was not available for the evaluation of a potent mu...
Abnormalities of the tumour vasculature and their consequences on the microenvironment of tumour cells impact on tumour progression and response to both blood-borne anti-cancer agents and radio-therapy, as well as making tumour blood vessels a target for therapy in their own right. Intravital microscopy of experimental tumours, most commonly grown...
The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by d...
This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H3 receptors (RO) in healthy human volunteers.
PET scans were obtained after i.v. administration of the H3 -specific radioligand [(11) C]GSK189254. Each subject was scanned befor...
Mathematical models are required to estimate kinetic parameters of [1-(13) C] pyruvate-lactate interconversion from magnetic resonance spectroscopy data. One- or two-way exchange models utilizing a hypothetical approximation to the true arterial input function (AIF), (e.g. an ideal 'box-car' function) have been used previously. We present a method...
The characterisation of a pharmacokinetic-receptor occupancy (PK-RO) relationship derived from a PET study is typically modelled in a conventional non-linear least squares (NLLS) framework. In the present work, we explore the application of a non-linear mixed effects approach (NLME) and compare this with NLLS estimation (using both naive pooled dat...
The evaluation of drug pharmacodynamics and early tumour response are integral to current clinical trials of novel cancer therapeutics to explain or predict long term clinical benefit or to confirm dose selection. Tumour vascularity assessment by positron emission tomography could be viewed as a generic pharmacodynamic endpoint or tool for monitori...
The development of a PET radioligand for imaging 5-hydroxytryptamine (5-HT) 6 receptors in the brain would, for the first time, enable in vivo imaging of this target along with assessment of its involvement in disease pathophysiology. In addition, such a tool would assist in the development of novel drugs targeting the 5-HT6 receptor.
On the basis...
There is growing recognition of the importance of integrating drug occupancy data acquired by positron emission tomography (PET) with the plasma pharmacokinetics of the drug, in order to establish proper dose selection in subsequent clinical trials. Here we present a study in human subjects of the occupancy of NK(1) receptors achieved following dif...
Here we describe methods for application of quantitative fluorodeoxyglucose positron emission tomography ([ 18F]FDG-PET) measures of brain glucose metabolism in multi-centre clinical trials for Alzheimer's disease. We validated methods and demonstrated their use in the context of a treatment trial with the PPARγ agonist Rosiglitazone XR versus plac...
Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Sec...
Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dos...
The histamine H(3) receptor is implicated in the pathophysiology of several central nervous system disorders. N-methyl-6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotamide (GSK189254) is a highly potent, selective, and brain-penetrant H(3) receptor antagonist. Previous studies in the pig using PET have shown that (11)C-GSK189254...
Background:
[(11)C]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT(2A) receptor quantification in vivo. Studies suggest that [(11)C]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses.
Methods:
Fi...
Positron emission tomography (PET) is an imaging technique that is used to investigate ligand-receptor binding in the living brain and to determine the time course of plasma concentration/receptor occupancy (RO). The purpose of this work was to demonstrate the added value of an adaptive-optimal design for PET scan timings and dose selection over tr...
Respiratory-induced diaphragm mismatch between positron emission tomography (PET) and computed tomography (CT) has been identified as a source of attenuation-correction artifact in cardiac PET. Diaphragm tracking in gated PET could therefore form part of a mismatch correction technique, where a single CT is transformed to match each PET frame. To i...
The histamine H(3) receptor is a G-protein-coupled presynaptic auto- and heteroreceptor whose activation leads to a decrease in the release of several neurotransmitters including histamine, acetycholine, noradrenaline, and dopamine. H(3) receptor antagonists such as 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridineca...
Quantitative estimation of neuroreceptor occupancy by exogenous drugs using positron emission tomography is based on the reduction in the total volume of distribution (V(T)) of site-specific radioligands after drug administration. An estimate of the distribution volume of free and nonspecifically bound radioligand (V(ND)) is also required to distin...
This systematic review describes human molecular imaging studies which have investigated alterations in extracellular DA levels during performance of behavioral tasks. Whilst heterogeneity in experimental methods limits meta-analysis, we describe the advantages and limitations of different methodological approaches. Interpretation of experimental r...
Tissue blood flow rate (F) is a critical parameter for assessing functional efficiency of a blood vessel network following angiogenesis. This chapter aims to provide the principles behind estimation of F and a practical approach to its determination in laboratory animals using small, readily diffusible, and metabolically inert radiotracers. The met...
Hypoxia increases cerebral blood flow (CBF), but it is unknown whether this increase is uniform across all brain regions. We used H(2)(15)O positron emission tomography imaging to measure absolute blood flow in 50 regions of interest across the human brain (n = 5) during normoxia and moderate hypoxia. Pco(2) was kept constant ( approximately 44 Tor...
To develop an image processing-based method to quantify the rate of extravasation of fluorescent contrast agents from tumor microvessels, and to investigate the effect of the tumor vascular disrupting agent combretastatin A-4-P (CA-4-P) on apparent tumor vascular permeability to 40 kDa fluorescein isothiocyanate (FITC) labeled dextran.
Extravasatio...
An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.
The positron emission tomography (PET) ligand [(11)C]MDL 100,907 has previously been introduced to image the serotonin 2A (5-HT(2A)) receptor in human brain. The aim of this work was to contribute to the verification of the tracer kinetic modelling in human studies. Five healthy volunteers were scanned twice after intravenous bolus injection of app...
With the aim of characterizing radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) as a SPECT ligand for subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), tracer kinetic compartmental analyses were compared with the tissue ratio method (TR). The pseudoequilibrium interval...
As part of the radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) characterization study, ketanserin challenges were performed on healthy volunteers with the aim of assessing the specificity of (123)I-R91150 binding to subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), the...
There is a growing interest in the application of imaging techniques to
drug discovery and development to enable earlier decisions to be made on
the suitability of a given drug for the treatment of disease in humans.
PET has the ability to image pharmacological functions in vivo in
conscious humans and is ideally suited to this task. Either the dru...
Positron emission tomography (PET), as an in vivo pharmacological imaging tool in experimental medicine, is playing an increasing role in drug development. There are two areas where PET is particularly useful in this respect, namely biodistribution and drug occupancy studies. Radiotracer design, the properties of the molecular targets which can be...
Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence.
We used positron emission tomography (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, mi...
Cyclic AMP (cAMP) is a continually produced nucleotide which is inactivated by hydrolysis to 5'AMP via phosphodiesterase 4 (PDE4) enzymes. Rolipram is a selective PDE4 inhibitor which exists in two enantiomeric forms, R(-) and S(+). Both of these enantiomers have previously been labelled with carbon-11 and used as positron emission tomography (PET)...
Most quantitative dynamic PET studies of radioligand binding to neuroreceptor sites in brain are analysed using models derived from a standard three-tissue compartment model. The full model has the advantage that the individual rate constants (microparameters) can be readily interpreted in terms of physiological and pharmacological properties of th...
Positron emission tomography (PET) is a quantitative in vivo tracer technique, enabling images of the distribution of biochemical, physiological and pharmacological functions in living tissue, at a resolution of a few millimetres. Applications include the imaging of blood flow rate, metabolic rate and neuroreceptor distribution and function. These...
Statistics is nowadays the customary language of functional imaging. It is common to express an experimental setting as a set of null hypotheses over complex models and to present results as maps of p-values derived from sophisticated probability distributions. However, the growing interest in the development of advanced statistical algorithms is n...
A non-invasive alternative to arterial blood sampling for the generation of a blood input function for brain positron emission tomography (PET) studies is presented. The method aims to extract the dimensions of the blood vessel directly from PET images and to simultaneously correct the radioactivity concentration for partial volume and spillover. T...
We have previously performed quantitative kinetic modeling of [(123)I]CNS 1261, a new SPET ligand for the MK801 intrachannel site of the NMDA receptor. We now report a bolus-infusion protocol, which eliminates the need for arterial blood sampling. Dynamic SPET scanning and venous blood sampling were performed in 7 healthy volunteers. Good agreement...
Compartmental models are widely used for the mathematical modelling of dynamic studies acquired with positron emission tomography (PET). The numerical problem involves the estimation of a sum of decaying real exponentials convolved with an input function. In exponential spectral analysis (SA), the nonlinear estimation of the exponential functions i...
Typical neuroimaging studies place great emphasis on not only the estimation but also the standard error estimates of underlying parameters derived from a temporal model. This is principally done to facilitate the use of t-statistics. Due to the spatial correlations in the data, it can often be more advantageous to interrogate models in the wavelet...
Recent studies of limbic cortical dopamine D(2) receptor occupancy by clozapine using high-affinity PET and SPET radioligands have produced conflicting findings. It has been suggested that these divergent findings are due to between-study differences in the method used to estimate D(2) receptor-binding potential. We compared different methods for e...
N-(1-napthyl)-N'-(3-[(123)I]-iodophenyl)-N-methylguanidine ([(123)I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [(123)I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity...
This article deals with the problem of model selection for the mathematical description of tracer kinetics in nuclear medicine. It stems from the consideration of some specific data sets where different models have similar performances. In these situations, it is shown that considerate averaging of a parameter's estimates over the entire model set...
This paper describes a new filter for parametric images obtained from dynamic positron emission tomography (PET) studies. The filter is based on the wavelet transform following the heuristics of a previously published method that are here developed into a rigorous theoretical framework. It is shown that the space-time problem of modeling a dynamic...
A kinetic modeling approach for the quantification of in vivo tracer studies with dynamic positron emission tomography (PET) is presented. The approach is based on a general compartmental description of the tracer's fate in vivo and determines a parsimonious model consistent with the measured data. The technique involves the determination of a spar...
There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The alpha5-containing subtype is highly expressed in the hippocampus, and selective alpha5 inverse agonists (which decrease tonic GABA inhibition) are being developed as p...
Partial Volume E#ects in PET lead to quantitative under and over estimations of the regional concentrations of radioactivity in reconstructed images and corresponding errors in derived functional or parametric images. The limited resolution of PET leads to "Tissue Fraction" e#ects, reflecting underlying tissue heterogeneity, and "Spillover" e#ects...
Physiological quantification of dynamic PET data requires the determination of an input function, preferably from plasma. A compartmental model relating a parent radiotracer, its radiolabelled metabolites and their exchange between plasma and erythrocytes is presented. This model allows for the time course of radioactivity measured in whole blood t...
We present a region template and a protocol for transforming that template to define anatomical volumes of interest (VOIs) in the human brain without operator intervention, based on software contained in the SPM99 package (Statistical Parametric Mapping, Wellcome Department of Cognitive Neurology, London, UK). We used an MRI of a reference brain to...
We calculated [(11)C]flumazenil volume of distribution ([(11)C]FMZ-V(d)) after correction for partial volume effect in 10 patients with malformations of cortical development (MCDs) and partial seizures, to quantify the GABA(A)-central benzodiazepine receptor complex. Abnormal grey matter and adjacent or overlying cortex were outlined individually a...
Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined with positron emission tomography scanning. However, the data obtained are of limited value because of the inability to distinguish catabolites (inactive species) from parent 5-FU and anabolites (cytotoxic species). In this paper, we have blocked 5-FU ca...
The current article presents theory for compartmental models used in positron emission tomography (PET). Both plasma input models and reference tissue input models are considered. General theory is derived and the systems are characterized in terms of their impulse response functions. The theory shows that the macro parameters of the system may be...
To characterize abnormalities in neocortical central benzodiazepine receptor (cBZR) binding in patients with mesial temporal lobe epilepsy (mTLE) with unilateral hippocampal sclerosis (HS) using [(11)C]-flumazenil-(FMZ) PET and complementary voxel-based and quantitative volume-of-interest (VOI) methods.
The authors studied 13 control subjects and 1...