Four decades of mapping and quantifying neuroreceptors at work in vivo by positron emission tomography

Decryption of brain images is the basis for the necessary translation of the findings from imaging to information required to meet the demands of clinical intervention. Tools of brain imaging, therefore, must satisfy the conditions dictated by the needs for interpretation in terms of diagnosis and prognosis. In addition, the applications must serve as fundamental research tools that enable the understanding of new therapeutic drugs, including compounds as diverse as antipsychotics, antidepressants, anxiolytics, and drugs serving the relief of symptoms from neurochemical disorders as unrelated as multiple sclerosis, stroke, and dementia. Here we review and explain the kinetics of methods that enable researchers to describe the brain\u27s work and functions. We focus on methods invented by neurokineticists and expanded upon by practitioners during decades of experimental work and on the methods that are particularly useful to predict possible future approaches to the treatment of neurochemical disorders. We provide an overall description of the basic elements of kinetics and the underlying quantification methods, as well as the mathematics of modeling the recorded brain dynamics embedded in the images we obtai

Quantification methods for brain imaging with novel and repurposed PET tracers

The number of people suffering from brain disorders is annually increasing. Knowledge about the molecular processes in the healthy and diseased brain is essential for a better understanding of disease conditions, treatment selection, and drug development. Positron emission tomography (PET) is a noninvasive imaging technique that can be used to acquire information about processes that are essential for normal brain functioning, but are altered in neurodegenerative diseases. Quantitative information about specific targets inside the brain, such as the density, activity, or occupancy of particular enzymes, transporters, or receptors, can be obtained by pharmacokinetic modeling of PET data. In the present study, we assessed quantification methods for brain imaging with novel and repurposed PET tracers. A PET tracer for inflammation in the brain, called [11C]SC-560, was evaluated, but overexpression of the inflammatory marker COX-1, could not be detected in the inflamed rat brain. Thus, more efforts to find an appropriate tracer are required. Next, we determined the optimal method for quantification of histamine H3 receptors in the rat brain, using PET and the radiotracer [11C]GSK-189254. Blockade of these receptors may improve cognition in patients with dementia. [11C]GSK-189254 PET and [11C]raclopride PET were subsequently used to measure the dose-dependent occupancy of histamine H3 and dopamine D2 receptors in the brain of living rats by the investigational drug AG-0029. D2 receptors play an important role in motor control. Since AG-0029 blocks histamine H3 receptors and stimulates dopamine D2 receptors, AG-0029 is a candidate drug for treatment of Parkinson disease. Finally, we evaluated the feasibility of quantifying the expression of estrogen receptors in the brains of post-menopausal women with [18F]FES PET. We were able to detect estrogen receptors in brain regions with a high density of the receptor (i.e., the pituitary). The methods described in this study may be used to enhance knowledge about the brain, the treatment of brain diseases and the development of novel drugs

Kinetic modeling and parameter estimation of TSPO PET imaging in the human brain

PURPOSE: Translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET) is widely used in research studies of brain diseases that have a neuro-immune component. Quantification of TSPO PET images, however, is associated with several challenges, such as the lack of a reference region, a genetic polymorphism affecting the affinity of the ligand for TSPO, and a strong TSPO signal in the endothelium of the brain vessels. These challenges have created an ongoing debate in the field about which type of quantification is most useful and whether there is an appropriate simplified model. METHODS: This review focuses on the quantification of TSPO radioligands in the human brain. The various methods of quantification are summarized, including the gold standard of compartmental modeling with metabolite-corrected input function as well as various alternative models and non-invasive approaches. Their advantages and drawbacks are critically assessed. RESULTS AND CONCLUSIONS: Researchers employing quantification methods for TSPO should understand the advantages and limitations associated with each method. Suggestions are given to help researchers choose between these viable alternative methods

지연가역 신경수용체 결합 파라메트릭 영상화를 위한 동적 뇌 PET 기반 비침습적 이중도표분석법

학위논문 (박사)-- 서울대학교 대학원 : 뇌인지과학과, 2016. 2. 이재성.Tracer kinetic modeling in dynamic positron emission tomography (PET) has been widely used to investigate characteristic distribution pattern or dysfunction of neuroreceptors in brain diseases, by offering a unique tool for generating images of quantitative parameters (or parametric imaging) of neuroreceptor binding. Graphical analysis (GA) is a major technique of parametric imaging, and is based on a simple linear regression model that is linearized and further simplified from a more complex general compartment model. Although each simple model of various GA methods enables very desirable parametric imaging, it depends on several assumptions that are commonly hard to satisfy simultaneously in parametric imaging for slow kinetic tracers, leading to error in parameter estimates. A combination of two GA methods, a bi-graphical analysis, may improve such intrinsic limitation of GA approaches by taking full advantage of spatiotemporal information captured in dynamic PET data and diverse strengths of individual GA methods. This thesis focuses on a bi-graphical analysis for parametric imaging of reversible neuroreceptor binding. Firstly, I provide an overview of GA-based parametric image generation with dynamic neuroreceptor PET data. The associated basic concepts in tracer kinetic modeling are presented, including commonly used compartment models and major parameters of interest. Then, technical details of GA approaches for reversible and irreversible radioligands are described considering both arterial-plasma-input-based (invasive) and reference-region-input-based (noninvasive) modelstheir underlying assumptions and statistical properties are described in view of parametric imaging. Next, I present a novel noninvasive bi-graphical analysis for the quantification of a reversible radiotracer binding that may be too slow to reach relative equilibrium (RE) state during PET scans. The proposed method indirectly implements the conventional noninvasive Logan plot, through arithmetic combination of the parameters of two other noninvasive GA methods and the apparent tissue-to-plasma efflux rate constant for the reference region (k_2^'). I investigate its validity and statistical properties, by performing a simulation study with various noise levels and k_2^' values, and also evaluate its feasibility for [18F]FP-CIT PET in human brain. The results reveal that the proposed approach provides a binding-parameter estimation comparable to the Logan plot at low noise levels while improving underestimation caused by non-RE state differently depending on k_2^'. Furthermore, the proposed method is able to avoid noise-induced bias of the Logan plot at high noise levels, and the variability of its results is less dependent on k_2^' than the Logan plot. In sum, this approach, without issues related to arterial blood sampling if a pre-estimated k_2^' is given, could be useful in parametric image generation for slow kinetic tracers staying in a non-RE state within a PET scan.Chapter 1 Introduction 1 1.1 Tracer Kinetic Modeling in PET 1 1.2 Regional versus Voxel-wise Quantification 2 1.3 Requirements for Parametric Imaging 3 1.4 Graphical Analysis 4 1.5 Thesis Statement and Contributions 5 1.6 Organization of the Thesis 6 Chapter 2 Basic Theory in Tracer Kinetic Modeling 8 2.1 Dynamic PET Acquisition 8 2.2 Compartmental Models 11 2.3 Parameters of Interest in Neuroreceptor Study 14 2.4 Limitations in Parametric Image Generation 18 Chapter 3 Overview of Graphical Analysis 20 3.1 General Characteristics 20 3.2 Reversible Radioligand Models 25 3.2.1 Logan Plot 25 3.2.2 Relative Equilibrium-based Graphical Plot 31 3.2.3 Ito Plot 36 3.3 Irreversible Radioligand Models 39 3.3.1 Invasive Gjedde-Patlak Plot 39 3.3.2 Noninvasive Gjedde-Patlak Approaches 40 Chapter 4 Noninvasive Bi-graphical Analysis for the Quantification of Slowly Reversible Radioligand Binding 43 4.1 Background 43 4.2 Materials and Methods 45 4.2.1 Invasive RE-GP Plots 45 4.2.2 Noninvasive GA Approaches 47 4.2.3 Noninvasive RE-GP Plots 49 4.2.4 Computer Simulations 51 4.2.5 Human [18F]FP-CIT PET Data 52 4.3 Results 54 4.3.1 Regional Time-activity Curves and Graphical Plots 54 4.3.2 Simulation Results 59 4.3.3 Application to Human Data 60 4.4 Discussion 66 4.4.1 Characteristics of [18F]FP-CIT PET Data 67 4.4.2 Kinetic Methods for [18F]FP-CIT PET 67 4.4.3 Correction for NRE Effects 68 4.4.4 Linearity Condition 69 4.4.5 Advantages over the Noninvasive Logan plot 69 4.4.6 Comparison with the SRTM 71 4.4.7 Simulation Settings 72 4.4.8 Noninvasiveness 74 Chapter 5 Summary and Conclusion 76 Bibliography 77 초 록 97Docto

Kinetic Modelling in Human Brain Imaging

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Molecular imaging of dopamine synthesis and release

Positron emission tomography (PET) can be used to measure striatal dopamine synthesis and release, both of which have been shown to be elevated in schizophrenia. One study has demonstrated that first degree relatives of schizophrenia patients exhibit increased dopamine synthesis capacity, suggesting this could be an endophenotype or susceptibility marker. However, the specific relation to schizophrenia was not tested, as the index cases were not studied. In this thesis, I directly tested the hypothesis that both members of twin pairs discordant for schizophrenia show similar increases in dopamine synthesis capacity. I found that striatal dopamine synthesis capacity is not elevated in individuals at genetic risk of schizophrenia or in stable patients with chronic schizophrenia, suggesting that it is not a vulnerability marker for schizophrenia, and is associated with active psychosis only. I also tested whether dopamine synthesis capacity is elevated in otherwise healthy people who report hallucinations. No elevation was found, suggesting that the underlying neurobiology is distinct from schizophrenia. I then considered whether it would be possible to examine similar relationships with measurements of dopamine release. Methodologies for this measurement were still limited: antagonist radioligands such as [11C] raclopride have been used, but the dynamic range for the measure is small, confounding precision. I hypothesised that agonist radioligands could provide a more sensitive measure. [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([11C]-(+)-PHNO) is a D2/D3 agonist PET radioligand. I directly compared the sensitivity of [11C]-(+)-PHNO to amphetamine challenge with that of the antagonist ligand [11C] raclopride. Mass carry-over and cerebellar binding were potential problems with [11C]-(+)-PHNO. I therefore designed a study to quantify these factors. I found that [11C]-(+)-PHNO is superior to [11C]raclopride for studying acute fluctuations in dopamine in the striatum. Use of [11C]-(+)-PHNO will allow quantification of smaller changes in dopamine release, although mass effects and displaceable cerebellar binding are potential confounding factors

Innovative Molecular Imaging for Clinical Research, Therapeutic Stratification, and Nosography in Neuroscience.

Over the past few decades, several radiotracers have been developed for neuroimaging applications, especially in PET. Because of their low steric hindrance, PET radionuclides can be used to label molecules that are small enough to cross the blood brain barrier, without modifying their biological properties. As the use of 11C is limited by its short physical half-life (20 min), there has been an increasing focus on developing tracers labeled with 18F for clinical use. The first such tracers allowed cerebral blood flow and glucose metabolism to be measured, and the development of molecular imaging has since enabled to focus more closely on specific targets such as receptors, neurotransmitter transporters, and other proteins. Hence, PET and SPECT biomarkers have become indispensable for innovative clinical research. Currently, the treatment options for a number of pathologies, notably neurodegenerative diseases, remain only supportive and symptomatic. Treatments that slow down or reverse disease progression are therefore the subject of numerous studies, in which molecular imaging is proving to be a powerful tool. PET and SPECT biomarkers already make it possible to diagnose several neurological diseases in vivo and at preclinical stages, yielding topographic, and quantitative data about the target. As a result, they can be used for assessing patients' eligibility for new treatments, or for treatment follow-up. The aim of the present review was to map major innovative radiotracers used in neuroscience, and explain their contribution to clinical research. We categorized them according to their target: dopaminergic, cholinergic or serotoninergic systems, β-amyloid plaques, tau protein, neuroinflammation, glutamate or GABA receptors, or α-synuclein. Most neurological disorders, and indeed mental disorders, involve the dysfunction of one or more of these targets. Combinations of molecular imaging biomarkers can afford us a better understanding of the mechanisms underlying disease development over time, and contribute to early detection/screening, diagnosis, therapy delivery/monitoring, and treatment follow-up in both research and clinical settings

Imaging of opioid receptors in the central nervous system

In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of μ-, κ and δ-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation—mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs—have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging