Quantitative Analysis and Comparison Study of [18F]AlF-NOTA-PRGD2, [18F]FPPRGD2 and [68Ga]Ga-NOTA-PRGD2 Using a Reference Tissue Model

With favorable pharmacokinetics and binding affinity for αvβ3 integrin, 18F-labeled dimeric cyclic RGD peptide ([18F]FPPRGD2) has been intensively used as a PET imaging probe for lesion detection and therapy response monitoring. A recently introduced kit formulation method, which uses an 18F-fluoride-aluminum complex labeled RGD tracer ([18F]AlF-NOTA-PRGD2), provides a strategy for simplifying the labeling procedure to facilitate clinical translation. Meanwhile, an easy-to-prepare 68Ga-labeled NOTA-PRGD2 has also been reported to have promising properties for imaging integrin αvβ3. The purpose of this study is to quantitatively compare the pharmacokinetic parameters of [18F]FPPRGD2, [18F]AlF-NOTA-PRGD2, and [68Ga]Ga-NOTA-PRGD2. U87MG tumor-bearing mice underwent 60-min dynamic PET scans following the injection of three tracers. Kinetic parameters were calculated using Logan graphical analysis with reference tissue. Parametric maps were generated using voxel-level modeling. All three compounds showed high binding potential (BpND = k3/k4) in tumor voxels. [18F]AlF-NOTA-PRGD2 showed comparable BpND value (3.75±0.65) with those of [18F]FPPRGD2 (3.39±0.84) and [68Ga]Ga-NOTA-PRGD2 (3.09±0.21) (p>0.05). Little difference was found in volume of distribution (VT) among these three RGD tracers in tumor, liver and muscle. Parametric maps showed similar kinetic parameters for all three tracers. We also demonstrated that the impact of non-specific binding could be eliminated in the kinetic analysis. Consequently, kinetic parameter estimation showed more comparable results among groups than static image analysis. In conclusion, [18F]AlF-NOTA-PRGD2 and [68Ga]Ga-NOTA-PRGD2 have comparable pharmacokinetics and quantitative parameters compared to those of [18F]FPPRGD2. Despite the apparent difference in tumor uptake (%ID/g determined from static images) and clearance pattern, the actual specific binding component extrapolated from kinetic modeling appears to be comparable for all three dimeric RGD tracers

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

© 2015 Springer-Verlag Berlin Heidelberg.Rationale: Central 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. Objectives: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Methods: Carbon-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-HT2A receptors, D2 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. Results: Oral 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-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 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 D2 receptors and 33 % of striatal serotonin transporters. Conclusions: The 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

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

Molecular Imaging

The present book gives an exceptional overview of molecular imaging. Practical approach represents the red thread through the whole book, covering at the same time detailed background information that goes very deep into molecular as well as cellular level. Ideas how molecular imaging will develop in the near future present a special delicacy. This should be of special interest as the contributors are members of leading research groups from all over the world

Développement d’outils quantitatifs pour le suivi par imagerie TEP/TDM de la réponse à la chimiothérapie et de sa toxicité

L’objectif de ce projet de doctorat est de développer des outils quantitatifs pour le suivi des traitements de chimiothérapie pour le cancer du sein et de leurs effets cardiotoxiques à l’aide de l’imagerie TEP dynamique. L’analyse cinétique en TEP dynamique permet l’évaluation de paramètres biologiques in vivo. Cette analyse peut être utilisé pour caractériser la réponse tumorale à la chimiothérapie et les effets secondaires néfastes qui peuvent en résulter. Le premier article de cette thèse décrit la mise au point des techniques d’analyse cinétique qui utilisent la fonction d’entrée d’un radiotraceur dérivé de l’image dynamique. Des corrections de contamination radioactive externe (épanchement) et de l’effet de volume partiel ont été nécessaires pour standardiser l’analyse cinétique et la rendre quantitative. Le deuxième article porte sur l’évaluation d’un nouveau radiotraceur myocardique. Le [indice supérieur 11]C-acétoacétate, un nouveau radiotraceur basé sur un corps cétonique, a été comparé au [indice supérieur 11]C-acétate, couramment utilisé en imagerie cardiaque TEP. L’utilisation de [indice supérieur 3]H-acétate et [indice supérieur 14]C-acétoacétate ont permis d’élucider la cinétique de ces traceurs depuis la fonction d’entrée et la captation par les mitochondries cardiaques qui reflète la consommation en oxygène, jusqu’à la libération de leurs principaux métabolites réciproques ([indice supérieur 3]H[indice inférieur 2]O et [indice supérieur 14]CO[indice inférieur 2]). Le troisième et dernier article de cette thèse présente l’intégration d’un modèle qui évalue la réserve cardiaque de perfusion et de consommation en oxygène. Un modèle de cardiomyopathie a été établi à l’aide d’un agent chimiothérapeutique contre le cancer du sein, la doxorubicine, reconnu comme étant cardiotoxique. Un protocole de repos/effort a permis d’évaluer la capacité d’augmentation de perfusion et de consommation en oxygène par le coeur. La démonstration d’une réserve cardiaque réduite caractérise la cardiotoxicité. La dernière contribution de cette thèse porte sur la mise au point de méthodes peu invasives pour mesurer la fonction d’entrée en modèle animal avec l’utilisation de l’artère caudale et un compteur microvolumétrique, la bi-modalité TEP/IRM dynamique avec le Gd-DTPA et l’établissement d’un modèle d’évaluation simultané de cardiotoxicité et réponse tumorale chez la souris. Le développement d’outils d’analyse TEP dans l’évaluation de la cardiotoxicité lors de traitements du cancer du sein permet de mieux comprendre la relation entre les dommages mitochondriaux et la diminution de la fraction d’éjection

Optimising the quantitative analysis in functional pet brain imaging

Patlak analysis techniques based on linear regression are often applied to positron emission tomography (PET) images to estimate a number of physiological parameters. The Patlak equation forms the basis for most extension works regarding graphical analysis of many tracers in quantitative PET measurements. Patlak analysis is primarily used to obtain the rate constant Ki, which represents the tracer transfer rate from plasma to the targeted tissue. One of the most common issues associated with Patlak analysis is the introduction of statistical noise, adopted originally from the images, that affects the slope of the graphical plot, leading to bias, and causes errors in the calculation of the rate constant Ki i. In this thesis, several statistical and noise reduction methods for 2 and 3 dimensional data are proposed and applied to simulated 18F-FDOPA brain images generated from a PET imaging simulator. The methods were applied to investigate whether their utilisation could reduce the bias and error caused by noisy images and improve the accuracy of quantitative measurements. Then, validation step extended to 18F-FDOPA PET images obtained from a clinical trial for Parkinson’s disease. The minimum averaged SE, SSE and the highest averaged reduction of noisy Ki values were found with the feasible generalised least squares (FGLS) model. Battle-Lemarie wavelet (BLW) showed significant change in data for the 3D PET images. Savitzky-Golay filtering (SGF) demonstrated significant change for most of the noise levels applied to 2D data. In clinical 18F-FDOPA images, the mean and standard deviation of standard error (SE) and sum-squared error (SSE) were significantly reduced in both baseline and after therapy groups. This work has the potential to be extended to other graphical analysis in quantitative PET data measurements