Thèses sur le sujet « Imaging PET »

Introduction Epilepsy is a heterogeneous collection of neurological diseases characterised clinically by recurrent seizures. Pre-clinical models implicate derangements in ligand-gated receptor-mediated neurotransmission in seizure generation and termination. In this thesis, the author quantified activated N-methyl D-aspartate- and opioid peptide receptor availability in adults with focal epilepsy. Methods This thesis consists of three positron emission tomography (PET) studies of adults with focal epilepsy, using [18F]GE-179 (activated NMDA receptors) and [11C]diprenorphine (DPN; opioid receptors) radioligands. A novel resolution-recovery technique, Structural Functional Synergistic-Resolution Recovery (SFS-RR), was applied to pre-existing paired [11C]DPN PET datasets acquired from adults with temporal lobe epilepsy (TLE). Activated NMDA receptor availability was quantified in adults with frequent interictal epileptiform discharges (IEDs), by regional compartmental modelling and model-free voxelwise analyses. Statistical parametric mapping was used to identify significant differences in volumes-of-distribution (VT) between populations. Results [18F]GE-179 had good brain extraction with a relatively homogeneous distribution and moderately-paced kinetics in grey matter. The two brain compartments, four rate-constants model best described the radioligand's kinetics in grey matter. Global increases in [18F]GE-179 VT were seen for seven of 11 participants with frequent IEDs. Focal increases in [18F]GE-179 VT of up to nearly 24% were also identified for three of the 11 participants. A post-ictal increase in [11C]DPN VT was identified in the ipsilateral parahippocampal gyrus. Discussion This first-in-man evaluation of [18F]GE-179 evidenced several properties that are desirable in PET radioligands, but the specificity of binding requires further characterisation. The results suggest focal increases in activated NMDA receptor availability in participants with refractory focal epilepsy, and also post-ictal increases in opioid peptide availability in the parahippocampal gyrus in TLE. Both findings may have pathophysiological relevance, and illustrate the potential of quantitative ligand PET with advanced post-processing to investigate changes in inhibitory and excitatory receptor systems in the epilepsies in vivo.

Optimization of Affibody molecules would allow for high contrast imaging of cancer associated surface receptors using molecular imaging. The primary aim of the thesis was to develop Affibody-based PET imaging agents to provide the highest possible sensitivity of RTK detection in vivo. The thesis evaluates the effect of radiolabelling chemistry on biodistribution and targeting properties of Affibody molecules directed against HER2 and PDGFRβ. The thesis is based on five published papers (I-V). Paper I. The targeting properties of maleimido derivatives of DOTA and NODAGA for site-specific labelling of a recombinant HER2-binding Affibody molecule radiolabelled with 68Ga were compared in vivo. Favourable in vivo properties were seen for the Affibody molecule with the combination of 68Ga with NODAGA. Paper II. The aim was to compare the biodistribution of 68Ga- and 111In-labelled HER2-targeting Affibody molecules containing DOTA, NOTA and NODAGA at the N-terminus. This paper also demonstrated favourable in vivo properties for Affibody molecules in combination with 68Ga and NODAGA placed on the N-terminus. Paper III.  The influence of chelator positioning on the synthetic anti-HER2 affibody molecule labelled with 68Ga was investigated. The chelator DOTA was conjugated either at the N-terminus, the middle of helix-3 or at the C-terminus of the Affibody molecules. The N-terminus placement provided the highest tumour uptake and tumour-to-organ ratios. Paper IV. The aim of this study was to evaluate if the 68Ga labelled PDGFRβ-targeting Affibody would provide an imaging agent suitable for PDGFRβ visualization using PET. The 68Ga labelled conjugate provided high-contrast imaging of PDGFRβ-expressing tumours in vivo using microPET as early as 2h after injection. Paper V. This paper investigated if the replacement of IHPEM with IPEM as a linker molecule for radioiodination of Affibody molecules would reduce renal retention of radioactivity. Results showed that the use of the more lipophilic linker IPEM reduced the renal radioactivity retention for radioiodinated Affibody molecules. In conclusion, this thesis clearly demonstrates that the labelling strategy is of great importance with a substantial influence on the targeting properties of Affibody molecules and should be taken under serious considerations when developing new imaging agents.

Medical imaging physics has advanced a lot in recent years, providing clinicians and researchers with increasingly detailed images that are well suited to be analyzed with a quantitative approach typical of hard sciences, based on measurements and analysis of clinical interest quantities extracted from images themselves. Such an approach is placed in the context of quantitative imaging. The possibility of sharing data quickly, the development of machine learning and data mining techniques, the increasing availability of computational power and digital data storage which characterize this age constitute a great opportunity for quantitative imaging studies. The interest in large multicentric databases that gather images from single research centers is growing year after year. Big datasets offer very interesting research perspectives, primarily because they allow to increase statistical power of studies. At the same time, they raised a compatibility issue between data themselves. Indeed images acquired with different scanners and protocols could be very different about quality and measures extracted from images with different quality might be not compatible with each other. Harmonization techniques have been developed to circumvent this problem. Harmonization refers to all efforts to combine data from different sources and provide users with a comparable view of data from different studies. Harmonization can be done before acquiring data, by choosing a-priori appropriate acquisition protocols through a preliminary joint effort between research centers, or it can be done a-posteriori i.e. images are grouped into a single dataset and then any effects on measures caused by technical acquisition factors are removed. Although the a-priori harmonization guarantees best results, it is not often used for practical and/or technical reasons. In this thesis I will focus on a-posteriori harmonization. It is important to note that when we consider multicentric studies, in addition to the technical variability related to scanners and acquisition protocols, there may be a demographic variability that makes single centers samples not statistically equivalent to each other. The wide individual variability that characterize human beings, even more pronounced when patients are enrolled from very different geographical areas, can certainly exacerbate this issue. In addition, we must consider that biological processes are complex phenomena: quantitative imaging measures can be affected by numerous confounding demographic variables even apparently unrelated to measures themselves. A good harmonization method should be able to preserve inter-individual variability and remove at the same time all the effects due acquisition technical factors. Heterogene ity in acquisition together with a great inter-individual variability make harmonization very hard to achieve. Harmonization methods currently used in literature are able to preserve only the inter-subjects variability described by a set of known confounding variables, while all the unknown confounding variables are wrongly removed. This might lead to incorrect harmonization, especially if the unknown confounders play an important role. This issue is emphasized in practice, as sometimes happens that demographic variables that are known to play a major role are unknown. The final goal of my thesis is a proposal for an harmonization method developed in the context of amyloid Positron Emission Tomography (PET) which aim to remove the effects of variability induced by technical factors and at the same time are able to keep all the inter-individual differences. Since knowing all the demographic confounders is almost impossible, both practically and a theoretically, my proposal does not require the knowledge of these variables. The main point is to characterize image quality through a set of quality measures evaluated in regions of interest (ROIs) which are required to be as independent as possible from anatomical and clinical variability in order to exclusively highlight the effect of technical factors on images texture. Ideally, this allows to decouple the between-subjects variability from the technical ones: the latter can be directly removed while the former is automatically preserved. Specifically, I defined and validated 3 quality measures based on images texture properties. In addition I used a quality metric already existing, and I considered the reconstruction matrix dimension to take into account image resolution. My work has been performed using a multicentric dataset consisting of 1001 amyloid PET images. Before dealing specifically with harmonization, I handled some important issues: I built a relational database to organize and manage data and then I developed an automated algorithm for images pre-processing to achieve registration and quantification. This work might also be used in other imaging contexts: in particular I believe it could be applied in fluorodeoxyglucose (FDG) PET and tau PET. The consequences of harmonization I developed have been explored at a preliminary level. My proposal should be considered as a starting point as I mainly dealt with the issues of quality measures, while the harmonization of the variables in itself was done with a linear regression model. Although harmonization through linear models is often used, more sophisticated techniques are present in literature. It would be interesting to combine them with my work. Further investigations would be desirable in future.

Fra le tecniche per lo studio dell’ imaging metabolico ci sono l’ MRI e la PET: l’ MRI fornisce informazioni strutturali e funzionali attraverso immagini caratterizzate da un’ ottima risoluzione spaziale e dalla possibilità di discriminare i vari tessuti molli: in particolare nelle applicazioni cerebrali consente di discriminare al meglio la sostanza bianca da quella grigia; la PET è una tecnica per lo studio dell' imaging metabolico molto utilizzata nella pratica clinica data la sua alta sensibilità nel rilevamento del tracciante e la sua capacità di quantificazione della sua distribuzione con una risoluzione spaziale che però è inferiore all’ MRI. La combinazione di dati eterogenei acquisiti con le due diverse metodiche permette di ottenere informazioni complementari di aiuto sia per la diagnosi clinica che per lo studio dei meccanismi patologici alla base di molte patologie. La combinazione è possibile utilizzando due approcci: attraverso la co-registrazione dei due tipi di immagini che permette di fondere insieme le informazioni provenienti da uno stesso paziente, acquisite in due sessioni distinte di PET e MR, via software o attraverso l’ uso di scanner ibridi che integrano le due modalità in un unico sistema hardware. Mentre da un punto di vista economico i moderni scanner ibridi risultano più onerosi, d’ altro canto permettono di ottenere performance migliori e di diminuire sia le tempistiche legate al post-processing dei dati acquisiti che la durata della scansione, migliorando il comfort del paziente. In questa tesi sono analizzati i due approcci di combinazione attraverso il confronto fra la procedura di co-registrazione e le acquisizioni di imaging ibrido PET-MR. Le due metodiche sono analizzate sotto il profilo tecnico-fisico e della procedura di post-processing dei dati acquisiti, valutando anche l' aspetto economico, logistico e di comfort del paziente e le prospettive future che potrebbero migliorare entrambi gli approcci.

Recent interests in computer based tools and simulations for PET imaging studies have been a leading source for many new developments. A strong emphasis in these studies has been to improve and optimize the PET scanners for better image quality and quantification of related system parameters. In this project, an attempt has been made to develop a Matlab tool intended to be of educational nature for new students where one can perform demonstration of PET-like imaging in a simple and quick way. This demonstration tool utilizes a high resolution, voxel based digital brain (Zubal) phantom as a primary study object. A tumor of specific size is defined by the user on a chosen slice of the phantom. The output images from this tool show the exact location of the predefined tumor. The algorithm attempts to estimate the positron emission direction, positron range distribution and photon detection in a circular geometry. Additional attempt has been made to estimate certain statistical parameters against a specific amount of radiotracer uptake. These include spatial resolution, photons count, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the ultimate PET image. Dependence of these estimated results by the tool on different system input parameters has been studied.

This dissertation is focused on applying aryltrifluoroborates (ArBF₃s) as PET imaging agents. Several aspects of this new ¹⁸F-labeling technique are addressed. These include the hydrolytic stability of heteroaryltrifluoroborates (HetArBF₃s), the fluoridation of arylboronic acids/esters and the radiosyntheses of several ¹⁸F-ArBF₃ labeled biomolecules for potential PET imaging applications. The solvolysis of several N-HetArBF₃s under physiological conditions was studied with ¹⁹F NMR spectroscopy in Chapter 2. All the N-HetArBF₃s tested therein displayed excellent solvolytic stability under physiological conditions. It is expected that these HetArBF₃s can be further applied as ¹⁸F-labeled PET imaging agents. In Chapter 3, a rapid fluoridation was carried out under conditions with low fluoride concentrations in a short reaction time (~ one hour). Via TLC-fluorescent densitometry, ¹⁹F NMR spectroscopy, and radio-HPLC, the fluoridation of different arylboronic acids/esters was investigated. It was found that the fluoridation occurs relatively rapidly in the presence of 3 to 5 equivalents of fluoride in acidic aqueous CH₃CN at room temperature. Under such conditions, radiochemical yields of 20-30% can be achieved. It was also noticed that arylboronates with acid-sensitive protecting groups could undergo fluoridations rapidly comparable to the arylboronic acids. In Chapter 4, marimastat, an MMP inhibitor, was labeled with an ¹⁸F-ArBF₃ to image breast cancer in mice. An unoptimized isolated radiochemical yield of ~ 1.5% and specific activities of 0.179 and 0.396 Ci/µmol were obtained within two hours including packaging. The blocking experiment suggested that the tumor uptake of Mar-¹⁸F-ArBF₃ was MMP specific. This one-step aqueous fluoridation was also applied to label a urea-based PSMA inhibitor (Chapter 5) and RGD-containing cyclopeptides (Chapter 8). Radiochemical yields ranging from 10% to 25% were obtained within one hour and good HPLC separation was achieved. In addition, a one-pot two-step labeling strategy was developed in Chapter 6 to label acid-sensitive biomolecules with ¹⁸F-ArBF₃s. The copper(I) catalyzed 1,3-dipolar cycloaddition was successfully used to conjugate ¹⁸F-ArBF₃s with biomolecules including oligonucleotides (Chapter 6), folate (Chapter 7), and a cyclic RGD-peptide (Chapter 8) with radiochemical yields of 20-30% over two steps in one hour.

In this thesis we consider the task of dynamic imaging using a gcPET system. Our technique is based on a mathematical method (developed for SPECT), which processes all dynamic projection data simultaneously instead of reconstructing a series of static images individually.  The algorithm was modified to account for the extra data that is obtained with gcPET (compared with SPECT).  The method was tested using simulated projection data for both a SPECT and a gcPET geometry.  These studies showed the ability of the code to reconstruct simulated data with a varying range of half-lives.  For SEPCT data the characteristic parameters of half-life (T_1/2) and initial activity (A₀) were reconstructed with a percentage error of 35.1%, and 40.8% (at 50 iterations) for a 2 minutes half-life, respectively.  The reconstruction of gcPET data showed improvement in half-life and activity compared to SPECT data by 27% and 31%, respectively (at 50 iterations). The method was also extended to enable reconstruction of images in which some regions increased in activity while other regions decreased.  Information of the spatial location of these images was provided in the form of a mask. The method was applied to experimental data.  These data were acquired using a dPET system and re-binned to the gcPET geometry.  The results, obtained from dynamic phantoms, showed that the characteristic behaviour could be recovered and that the code produced satisfactory dynamic images.  The method was also applied to data from a patient with a tumour.  Again, the reconstructed image showed good results compared to the dPET reconstruction.  Time activity curves showed a significant difference between the uptake of tumour and myocardium. Finally, we presented a method to deal with the situation where the activity in certain pixels decreases and then increases during the acquisition.

Positron Emission Tomography (PET) is emerging as a powerful method for imaging cancer through the design and development of new radiotracers. Antibodies have promising properties as ligands for targeting cancer, as they have the advantage of displaying high affinity for their respective receptors. However, the use of antibodies as radiotracers is limited to the use of long-lived isotopes, as these large biomolecules additionally display slow blood circulation and clearance. The use of short-lived isotopes such as 18F or 68Ga, in combination with antibodies, would provide the ideal balance between targetability and clearance. This may be achieved by use of a two-step pretargeting strategy, whereby a reactive tag is conjugated to the antibody and allowed to localise in the tissue to be imaged, before systemic administration of a chemical reporter (e.g. a labelled reactive partner) which allows the 'pretargeted' tissue to be imaged. The Strain-Promoted Azide/Alkyne Cycloaddition (SPAAC) reaction between cyclooctynes and azides was evaluated as an appropriate bioorthogonal reaction for application to a pretargeting strategy using short-lived isotopes. The synthesis of a library of cyclooctyne precursors was carried out, which were evaluated in terms of their reactivity with azides, and their suitability for in vivo applications. An 18F-labelled version of the SPAAC reaction was developed, demonstrating the ability of the reaction to be carried out under different conditions. This model reaction was translated to in vivo pretargeting using a cyclooctyne modified Herceptin monoclonal antibody and an 18F-labelled azide. These initial experiments indicated that the SPAAC reaction may not be fast enough to occur at the low concentrations which are found in vivo. The reaction was thoroughly examined in terms of kinetics at different concentrations, and a high concentration-dependence upon rate of reaction was confirmed. This was supported by a 68Ga-labelled SPAAC reaction, which was carried out using reportedly more reactive cyclooctynes than those used in the initial experiments. In general, the reaction showed a greater preference to be carried out in organic solvents such as acetonitrile, and under closer to physiological conditions the reactions were less likely to proceed. The Inverse-electron-Demand Diels-Alder (IeDDA) reaction between tetrazines and strained alkenes was evaluated as an alternative bioorthogonal reaction for demonstrating in vivo pretargeting. A series of 68Ga-labelled IeDDA reactions between a 68Ga-labelled tetrazine and a series of norbornene analogues demonstrated the superior reaction kinetics and biocompatibility of the IeDDA reaction. The initial translation of the IeDDA reaction to a proof-of-concept for pretargeting using cyclic RGD pentapeptides was initially unsuccessful, attributed to the surprisingly poor reactivity of norbornene-modified cyclic RGD pentapeptides towards a 68Ga-labelled tetrazine. The reaction between a 68Ga-labelled tetrazine and a Cetuximab antibody, which had been modified with the more reactive trans-cyclooctene (TCO) moeity, was successfully demonstrated. The hypothesised pretargeting strategy using this model reaction was achieved on high EGFR expressing cells, validating the IeDDA reaction in this context. These results suggested tantalising opportunities for application of the IeDDA reaction to in vivo pretargeting for PET imaging using short-lived isotopes such as 18F and 68Ga.

Amyloid PET imaging with [11C]PIB enabled detection of Aβ for the first time in vivo. However, [11C]PIB is a small molecule that binds only the insoluble Aβ plaque. Rather, the soluble Aβ aggregates are considered the cause of Alzheimer’s disease (AD). As such, a more sensitive and specific PET tracer is needed for tracking longitudinal AD pathology. Soluble Aβ aggregates likely interact with the metabotropic glutamate receptor 5 (mGluR5) to cause neurotoxic effects. However, with [11C]ABP688 PET we were unable to detect aberrant mGluR5 binding in AD mouse models, although we find elevated mGluR5 protein levels with immunoblotting. Antibodies are highly specific large molecules that can bind specifically to soluble Aβ aggregates, thus they can be a good marker for AD pathology. Unfortunately, due to their large size they cannot cross the blood-brain barrier (BBB). However, it is possible to shuttle antibodies into the brain by taking advantage of endogenous transporter systems on the BBB. By creating bispecific antibodies binding both to soluble Aβ aggregates and to the transferrin receptor (BBB target), we successfully transported the antibody into the brain and could visually detect soluble Aβ aggregates with PET. Recombinant expression further improved and optimized antibody design, creating smaller bispecific antibody-based constructs that had better pharmacokinetic properties allowing for earlier PET scanning (1 day instead of 3), and more sensitive signal. Lastly, using TCO-tetrazine click chemistry, we indirectly labeled our antibodies with fluorine-18, and could successfully perform PET already 11 h post-injection with a fluorine-18 labeled antibody.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 147-158).
Whole-brain neuroimaging is a key technique for studying brain function and connectivity. Recent advances in combining two imaging modalities - magnetic resonance imaging (MRI) and positron emission tomography (PET) - into one integrated scanner, have created the opportunity to explore the underlying neurochemistry of brain function in more detail. Imaging these dynamics plays an important role for understanding drug action and function of neurochemical pathways in the brain and is crucial, yet largely unexplored, for creating and evaluating treatment of neurological and psychiatric disorders. In this thesis, we first address technological challenges in simultaneous PET/MRI by designing, building and evaluating PET compatible MR probes for brain imaging, which enable highly sensitive dual modality imaging. We then develop simultaneous imaging methods with PET and functional MRI to assess and validate relationships between receptor occupancy and changes in brain activity due to pharmacological challenges targeting the dopamine system. Our results indicate that dopamine receptor occupancies and vascular responses are correlated in anatomical space and with pharmacological dose. Moreover, the temporal dynamics of the signals show that a direct neurovascular coupling between receptor occupancy and hemodynamics exists and that a temporal divergence between PET and fMRI can be used to investigate previously unexplored neurochemical parameters and adaptation mechanisms in vivo. Overall, our findings provide insight into dopaminergic receptor dynamics and their effects on high-level brain function, paving a way to address receptor-specific brain dysfunction effectively.
by Christin Y. Sander.
Ph. D.

In dual modality PET-CT imaging, respiratory motion can introduce blurring in PET images and create a spatial mismatch between the PET and CT datasets. Attenuation correction errors can result from this mismatch, which can produce severe artefacts that potentially alter the clinical interpretation of the images. Various approaches of reducing these effects have been developed. Many involve respiratory gated acquisitions which generally require a measure of the respiratory cycle throughout imaging. In this work, a retrospective respiratory gating technique was devel¬oped for both PET and CT which extracts the respiratory cycle from the acquired data itself, removing the requirement for hardware that measures respiration. This data-driven gating method was validated with phantom and patient data, and compared with a hardware based approach of gating. Extensions to the method facilitated the gating of multi-bed position, 3D clinical PET scans. Finally, 60 Ammonia cardiac PET/CT images were used to compare several different ap¬proaches of reducing respiratory induced attenuation correction errors and motion blur. The data-driven respiratory gating method accurately substituted a hardware based approach, and no significant difference was found between images gated with either methods. Gating 11 clinical 3D whole body PET images validated the extended data-driven gating methods and demonstrated successful combination of separate PET bed-positions. All evaluated approaches to reduce respiratory motion artefacts in cardiac imaging demonstrated an average improvement in PET-CT alignment. However, cases were found where alignment worsened and artefacts resulted. Fewer and less severe cases were produced when the 4D attenuation correction data was created from a 3D helical CT and PET derived motion fields. Full motion cor¬rection produced a small effect on average, however in this case no detrimental effects were found.

Dans cette thèse nous présentons l’imagerie trois gammas, où le système d’acquisition repose sur un émetteur bêta+ et gamma. La justification de l’imagerie 3-gamma est que les informations du détection du troisième gamma peuvent aider à fournir une meilleure localisation du point d’annihilation, permettant ainsi une meilleure qualité d’image et moins de dose délivrée au patient. Nous vous présentons le systéme 3-gamma XEMIS2, développé à Subatech, Nantes, qui est un détecteur basé sur Liquid Xenon, adapté à l’imagerie3-gamma grâce à son stopping power, ses caractéristiques de scintillation et sa géométrie continue. Le principe de la reconstruction d’image 3-gamma est basé sur l’intersection d’une LOR, obtenue à partir des photons de coïncidence, avec un cône Compton, déterminé par le troisième gamma. L’idée est de trouver l’intersection du cône et de la LOR et de l’utiliser pour localiser la position d’annihilation la plus probable sur la ligne, comme pour la différence en temps d’arrivé en TOF-PET. Nous présentons une étude de simulation GATE de deux phantoms (NEMA et Digimouse) pour évaluer les améliorations de la reconstruction d’image 3-gamma par rapport à la TEP conventionnelle, et nous étudions aussi la correction du range du positon, qui est important pour notre émetteur Sc44
In this thesis we present three-gamma imaging, where the acquisition system relies on a beta+ and gamma emitter. The rationale of 3-gamma imaging is that the third gamma detection information may help to provide better localization of the annihilation point, thus enabling higher image quality and fewer dose delivered to the patient. We present the 3-gamma system, theXEMIS2, developed at Subatech, Nantes, that is a LiquidXenon detector suitable for 3-gamma imaging due to its stopping power, its scintillation characteristics and its continuous geometry. The principle of 3-gamma image reconstruction is based on the intersection of a LOR, obtained from the coincidence photons, with a Compton cone, determined by the third gamma. The idea is to find the LOR\cone intersection and use it to locate the most probable annihilation position on the line,as for the time difference in TOF-PET. We present a complete GATE simulation study of two phantoms (similar-NEMA and Digimouse), to assess the improvements of 3-gamma image reconstruction over conventional PET and we study the positron range correction, which is important for our beta+gamma emitter, Sc44

Myocardial perfusion imaging (MPI) is an effective technique used to study the left ventricular ejection function (LVEF), myocardial perfusion, wall motion, and wall thickening. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are two modalities that can be used to quantify the left global and regional perfusion at rest and stress. While PET and SPECT rely on similar principles to produce images, important differences in instrumentation and experimental applications are dictated by inherent differences in their respective physics of radioactive decay. With a sensitivity > 90% in combination with a high specificity, PET is today the best available nuclear imaging technique for the diagnosis of coronary artery disease (CAD). The short half-life of the perfusion tracers in combination with highly sophisticated hard- and software enables rapid PET studies with high patient throughput. Rubidium-82 (82Rb) is a PET perfusion imaging agent that has a shot half-life of 76 seconds which enables multiple sequential data acquisitions in a short duration of time. It also reduces the number of false-positive SPECT scans and artifacts from soft tissue attenuation due to the routine application of attenuation correction. However 82Rb PET imaging is under-utilized clinically due to difficulty optimizing the imaging parameters. The major challenge of 82Rb imaging is determining when to begin the image acquisition post infusion, as imaging too early results in images with high background (low contrast), and imaging too late results in noisy images due to low count statistics. 82Rb rest/stress dynamic and gated data from 16 patients were available for analysis. The FWHM of the 82Rb infusion, LV cavity and LV myocardial uptake in time activity curves were generated and compared to isolate the dominant parameter in determining image quality. The measured and actual infusion-time correlated only at rest (r = 0.93, P = 0.006). Splitting-time at rest and stress correlated (r = 0.74, P = 0.09). But the study was not able to identify a single dominant parameter that would determine the image quality due to the unpredictable nature of hemodynamics during the vasodilatory induced cardiovascular stress. First pass radionuclide angiography (FPRNA) is the gold standard for quantification of ejection fraction. We examined the quantification of the ejection function (LVEF) to determine whether the gated 82Rb PET data, using quantitative gated SPECT (QGS), would accurately predict changes in the chamber volume and correlated the results with those obtained from FPRNA technique. There was a good correlation between the resting FPRNA data and resting gated 82Rb QGS data (r= 0.81, P=0.0005) showing that this method can be applied to 82Rb PET.99mTc SPECT was considered the gold standard for this study, as it is the most widely used technique for myocardial perfusion imaging. The under-perfused area of the myocardium is defined as defect. 99mTc agents, 18F-FDG, and 82Rb can all be used for cardiac imaging 1-7. However, count rates, energy and camera differences can yield image differences that are independent of the actual biological distribution. We examined whether PET with an 82Rb-labeled tracer would provide information on defect size similar to that provided by 99mTc SPECT, using a cardiac phantom in which the true defect size is known. Since 82Rb has such a short half-life (76 seconds), filling and imaging a phantom was going be a great challenge. Hence 124I which is a high-energy radioisotope like 82Rb, was used in this phantom study as a surrogate for 82Rb. Static cardiac phantom studies with 99mTc, 18F and 124I (surrogate for 82Rb) were conducted. The percent defect sizes were measured and compared with the true defect size. Our results demonstrated that at 45% threshold, the measured defect size was representative of true defect size for 99mTc SPECT data. Using this threshold as the standard, we smoothed the 18F and 124I PET data until the measured defect size for PET was representative of the true defect size. An optimal filter cutoff frequency (Butterworth filter, cutoff = 0.80 cycles/pixel, order=5 at 45% threshold for 124I or 82Rb) was found for the PET data within the range of values studied, and this frequency was higher than the clinical norm for SPECT data. Our results also illustrated that the measured SPECT defect size varied greatly depending on the thresholds used to define a defect, whereas measure PET defect size was relatively constant over the range of cutoffs tested7. The optimal cutoff may depend on defect size, patient variability, and noise level. When assessing myocardial defect size, physical properties need to be taken into consideration, particularly when comparing images obtained using different nuclides (i.e. 82Rb or 99mTc agent perfusion and 18F FDG viability).

Introduction The goal of this work is to advance the production and use of 52Mn (t½ = 5.6 d, β+: 242 keV, 29.6%) as a radioisotope for in vivo preclinical nuclear imaging. More specifically, the aims of this study were: (1) to measure the excitation function for the natCr(p,n)52Mn reaction at low energies to verify past results [1–4]; (2) to measure binding constants of Mn(II) to aid the design of a method for isolation of Mn from an irradiated Cr target via ion-exchange chromatography, building upon previously published methods [1,2,5–7]; and (3) to perform phantom imaging by positron emission tomography/magnetic resonance (PET/MR) imaging with 52Mn and non-radioactive Mn(II), since Mn has potential dual-modality benefits that are beginning to be investigated [8]. Material and Methods Thin foils of Cr metal are not available commercially, so we fabricated these in a manner similar to that reported by Tanaka and Furukawa [9]. natCr was electroplated onto Cu discs in an industrial-scale electroplating bath, and then the Cu backing was digested by nitric acid (HNO3). The remaining thin Cr discs (~1 cm diameter) were weighed to determine their thickness (~ 75–85 μm) and arranged into stacked foil targets, along with ~25 μm thick Cu monitor foils. These targets were bombarded with ~15 MeV protons for 1–2 min at ~1–2 μA from a CS-15 cyclotron (The Cyclotron Corporation, Berkeley, CA, USA). The beamline was perpendicular to the foils, which were held in a machined 6061-T6 aluminum alloy target holder. The target holder was mounted in a solid target station with front cooling by a jet of He gas and rear cooling by circulating chilled water (T ≈ 2–5 °C). Following bombardment, these targets were disassembled and the radioisotope products in each foil were counted using a high-purity Ge (HPGe) detector. Cross-sections were calculated for the natCr(p,n)52Mn reaction. Binding constants of Mn(II) were measured by incubating 54Mn(II) (t½ = 312 d) dichloride with anion- or cation-exchange resin (AG 1-X8 (Cl− form) or AG 50W-X8 (H+ form), respectively; both: 200–400 mesh; Bio-Rad, Hercules, CA) in hydrochloric acid (HCl) ranging from 10 mM-8 M (anion-exchange) and from 1 mM-1 M (cation-exchange) or in sulfuric acid (H2SO4) ranging from 10 mM-8 M on cation-exchange resin only. The amount of unbound 54Mn(II) was measured using a gamma counter, and binding constants (KD) were calculated for the various concentrations on both types of ion-exchange resin. We have used the unseparated product for preliminary PET and PET/MR imaging. natCr metal was bombarded and then digested in HCl, resulting in a solution of Cr(III)Cl3 and 52Mn(II)Cl2. This solution was diluted and imaged in a glass scintillation vial using a microPET (Siemens, Munich, Germany) small animal PET scanner. The signal was corrected for abundant cascade gamma-radiation from 52Mn that could cause random false coincidence events to be detected, and then the image was reconstructed by filtered back-projection. Additionally, we have used the digested target to spike non-radioactive Mn(II)Cl2 solutions for simultaneous PET/MR phantom imaging using a Biograph mMR (Siemens) clinical scanner. The phantom consisted of a 4×4 matrix of 15 mL conical tubes containing 10 mL each of 0, 0.5, 1.0, and 2.0 mM concentrations of non-radioactive Mn(II)Cl2 with 0, 7, 14, and 27 μCi (at start of PET acquisition) of 52Mn(II)Cl2 from the digested target added. The concentrations were based on previous MR studies that measured spin-lattice relaxation time (T1) versus concentration of Mn(II), and the activities were based on calculations for predicted count rate in the scanner. The PET/MR imaging consisted of a series of two-dimensional inversion-recovery turbo spin echo (2D-IR-TSE) MR sequences (TE = 12 ms; TR = 3,000 ms) with a wide range of inversion times (TI) from 23–2,930 ms with real-component acquisition, as well as a 30 min. list-mode PET acquisition that was reconstructed as one static frame by 3-D ordered subset expectation maximization (3D-OSEM). Attenuation correction was performed based on a two-point Dixon (2PD) MR sequence. The DICOM image files were loaded, co-registered, and windowed using the Inveon Research Workplace software (Siemens).

Nell'ambito della Diagnostica per Immagini, l'imaging ibrido sta assumendo un ruolo fondamentale in molte applicazioni cliniche, tra cui oncologia, neurologia e cardiologia. La possibilità di integrare informazioni complementari, funzionali e morfologiche, in un'unica immagine, permette di valutare con estrema accuratezza varie tipologie di malattie, diminuendo i tempi di acquisizione e i disagi per i pazienti. La risonanza magnetica, in sostituzione alla TAC nel sistema integrato PET/TC, introduce notevoli vantaggi quali l'acquisizione simultanea dei dati, l'ottimo contrasto dei tessuti molli, l'assenza di radiazioni ionizzanti e la correzione degli artefatti da movimento; ciò migliora l'accuratezza delle immagini e, di conseguenza, il processo diagnostico. Nonostante sia un interessante strumento di diagnostica e l'apice dello sviluppo tecnologico in imaging nucleare, vi sono alcune problematiche che ne impediscono la diffusa adozione, tra cui le interferenze reciproche tra le due modalità, i costi elevati e ancora una ridotta pubblicazione di articoli al riguardo.

Poly(ADP-ribose)polymerase-1 and -2 (PARP1/2) are nuclear proteins involved in DNA repair. Tumors with defects in homologous recombination, including BRCA1- and BRCA2-deficient cancers, have been shown to be sensitive to PARP inhibition. The Weissleder group has synthesized fluorescent and radioactive derivatives of the PARP1/2 inhibitor AZD2281. We hypothesized that fluorescent and radioactive AZD2281-based imaging agents would quantify PARP1/2 expression in vitro and in vivo. To test this hypothesis, a panel of pancreatic ductal adenocarcinoma and ovarian carcinoma cell lines were characterized by immunocytochemistry for PARP1/2 expression. AZD2281-derived fluorescence signal correlated with anti-PARP antibody fluorescence signal strength in vitro. Four cell lines representing a range of PARP1/2 expression levels were then xenografted into Nu/Nu mice. Mice bearing four tumor types each were imaged with AZD2281-derived imaging agents, sacrificed, and their tumors excised for stand-alone imaging and Western blot. AZD2281-derived signal correlated with tumor PARP1/2 expression determined by Western blot, indicating that PARP1/2 expression level is a determinant of fluorescent signal strength and SUVs of AZD2281-derived agents in vivo. These data indicate that AZD2281-derived agents are useful tools for quantifying intracellular PARP1/2 both in vitro and in vivo, which could one day enable prospective identification of tumors likely to respond to PARP inhibitors.

The limited spatial resolution in positron emission tomography (PET) images leads to difficulties to measure correct uptake in tumours. This is called partial volume effects (PVE) and can lead to serious bias, especially for small tumours. Correct uptake values are valuable for evaluating therapies and can be used as a tool for treatment planning. The purpose of this project was to evaluate two methods for compensating for PVE. Also, a method for tumour delineation in PET-images was evaluated. The methods were used on images reconstructed with two algorithms, VUE-point HD (VP HD) and VP SharpIR. The evaluation was performed using a phantom including fillable spheres which were used to simulate tumours of different sizes. The first method used for PVE compensation was an iterative deconvolution method which to some degree restores the spatial resolution in the images. The tumour uptake was measured with volumes of interest (VOIs) based on a percentage of the maximum voxel value. The second method was to use recovery coefficients (RCs) as correction factors for the measured activity concentrations. These were calculated by convolving binary images of tumours with the point spread function (PSF). The binary images were achieved both from computed tomography (CT) images and from PET images with a threshold method for tumour delineation. The threshold method was based on both tumour activity and background activity, and was also compared with a conventional threshold technique. The results showed that images reconstructed with VP SharpIR can be used for activity concentration measurements with good precision for tumours larger than 13mm diameter. Smaller tumours benefit from RCs correction. The threshold method for tumour delineation showed substantially better results compared to the conventional threshold method.
Den begränsade spatiella upplösningen i bilder från positronemissions-tomografi (PET) leder till svårigheter i att mäta korrekt upptag i tumörer. Detta kallas partiella volymseffekter (PVE) och kan leda till stora fel, speciellt för små tumörer. Korrekta upptagsvärden är värdefulla vid behandlingsutvärdering och kan användas som ett verktyg för att planera behandlingar. Syftet med detta projekt var att utvärdera två metoder för att kompensera för PVE. Även en metod för tumöravgränsning i PET-bilder utvärderades. Metoderna användes på bilder som rekonstruerats med två olika algoritmer, VUE-point HD (VP HD) och VP SharpIR. Utvärderingen utfördes med ett fantom med sfärer som fylldes med aktivitet och därmed simulerade tumörer av olika storlekar. Den första metoden för PVE-kompensation var en iterativ avfaltningsmetod som, i viss mån, återställer bildernas spatiella upplösning. Upptaget i tumörerna mättes som medelupptaget i s.k. ”volumes of interests” (VOI:ar) som baserades på andelar av maximala voxelvärdet. Den andra metoden byggde på användning av s.k. recovery coefficients (RCs) som korrektionsfaktorer för de uppmätta aktivitetskoncentrationerna. Dessa beräknades genom att falta binära bilder av tumörerna med punktspridningsfunktionen (PSF). De binära bilderna framställdes både från bilder tagna med datortomografi (computed tomography, CT) och från PET-bilder med en tröskelmetod för tumöravgränsning. Tröskelmetoden baserades både på aktiviteten i tumören och på bakgrundsaktiviteten. Den jämfördes också med en konventionell tröskelmetod. Resultaten visade att bilder som rekonstruerats med VP SharpIR kan användas för mätning av aktivitetskoncentration med god precision för tumörer större än 13mm diameter. För mindre tumörer är det bättre att använda RC:s. Tröskelmetoden för tumöravgränsning visade avsevärt bättre resultat jämfört med den traditionella tröskelmetoden.

There is always a need and drive to improve modern cancer care. Dynamic positron emission tomography (PET) offers the advantage of in vivo functional imaging, combined with the ability to follow the physiological processes over time. In addition, by applying tracer kinetic modeling to the dynamic PET data, thus estimating pharmacokinetic parameters associated to e.g. glucose metabolism, cell proliferation etc., more information about the tissue's underlying biology and physiology can be determined. This supplementary information can potentially be a considerable aid when it comes to the segmentation, diagnosis, staging, treatment planning, early treatment response monitoring and follow-up of cancerous tumors. We have found it feasible to use kinetic parameters for semi-automatic tumor segmentation, and found parametric images to have higher contrast compared to static PET uptake images. There are however many possible sources of errors and uncertainties in kinetic parameters obtained through compartment modeling of dynamic PET data. The variation in the number of detected photons caused by the random nature of radioactive decay, is of course always a major source. Other sources may include: the choice of an appropriate model that is suitable for the radiotracer in question, camera detectors and electronics, image acquisition protocol, image reconstruction algorithm with corrections (attenuation, random and scattered coincidences, detector uniformity, decay) and so on. We have found the early frame sampling scheme in dynamic PET to affect the bias and uncertainty in calculated kinetic parameters, and that scatter corrections are necessary for most but not all parameter estimates. Furthermore, analytical image reconstruction algorithms seem more suited for compartment modeling applications compared to iterative algorithms. This thesis and included papers show potential applications and tools for quantitative pharmacokinetic parameters in oncology, and help understand errors and uncertainties associated with them. The aim is to contribute to the long-term goal of enabling the use of dynamic PET and pharmacokinetic parameters for improvements of today's cancer care.
Det finns alltid ett behov och en strävan att förbättra dagens cancervård. Dynamisk positronemissionstomografi (PET) medför fördelen av in vivo funktionell avbilning, kombinerad med möjligheten att följa fysiologiska processer över tiden. Genom att därtill tillämpa kinetisk modellering på det dynamiska PET-datat, och därigenom skatta farmakokinetiska parametrar associerade till glukosmetabolism, cellproliferation etc., kan ytterligare information om vävnadens underliggande biologi och fysiologi bestämmas. Denna kompletterande information kan potentiellt vara till stor nytta för segmentering, diagnos, stadieindelning, behandlingsplanering, monitorering av tidig behandlingsrespons samt uppföljning av cancertumörer. Vi fann det möjligt att använda kinetiska parametrar för semi-automatisk tumörsegmentering, och fann även att parametriska bilder hade högre kontrast jämfört med upptagsbilder från statisk PET. Det finns dock många möjliga källor till osäkerheter och fel i kinetiska parametrar som beräknats genom compartment-modellering av dynamisk PET. En av de största källorna är det radioaktiva sönderfallets slumpmässiga natur som orsakar variationer i antalet detekterade fotoner. Andra källor inkluderar valet av compartment-modell som är lämplig för den aktuella radiotracern, PET-kamerans detektorer och elektronik, bildtagningsprotokoll, bildrekonstruktionsalgoritm med tillhörande korrektioner (attenuering, slumpmässig och spridd strålning, detektorernas likformighet, sönderfall) och så vidare. Vi fann att tidssamplingsschemat för tidiga bilder i dynamisk PET påverkar både fel och osäkerhet i beräknade kinetiska parametrar, och att bildkorrektioner för spridd strålning är nödvändigt för de flesta men inte alla parametrar. Utöver detta verkar analytiska bildrekonstruktionsalgoritmer vara bättre lämpade för tillämpningar som innefattar compartment-modellering i jämförelse med iterativa algoritmer. Denna avhandling med inkluderade artiklar visar möjliga tillämpningar och verktyg för kvantitativa kinetiska parametrar inom onkologiområdet. Den bidrar också till förståelsen av fel och osäkerheter associerade till dem. Syftet är att bidra till det långsiktiga målet att möjliggöra användandet av dynamisk PET och farmakokinetiska parametrar för att förbättra dagens cancervård.

In translational medicine, complementary functional and morphological imaging techniques are used extensively to observe physiological processes in vivo and to assess structural changes as a result of disease progression. The combination of magnetic resonance imaging (MRI) and positron emission tomography (PET) provides excellent soft tissue contrast from MRI with exceptional sensitivity and specificity from PET. This thesis explores the use of sequentially acquired PET and MR images to improve the quantification of small animal PET data. The primary focus was to improve image-based estimates of the arterial input function (AIF), which defines the amount of PET tracer within blood plasma over time. The AIF is required to produce physiological parameters quantifying key processes such as metabolism or perfusion from dynamic PET images. The gold standard for AIF measurement, however, requires serial blood sampling over the course of a PET scan, which is invasive in rat studies but prohibitive in mice due to small total blood volumes. To address this issue, the geometric transfer matrix (GTM) and recovery coefficient (RC) techniques were applied using anatomical MR images to enable the extraction of partial volume corrected image based AIFs from mouse PET images. A non-invasive AIF extraction method was also developed for rats, beginning with the optimization of an automated voxel selection algorithm to assist in extracting MR contrast agent signal time courses from dynamic susceptibility contrast (DSC) MRI data. This procedure was then combined with dynamic contrast enhanced (DCE) MRI to track a combined injection of Gadolinium-based contrast agent and PET tracer through the rat brain. By comparison with gold standard tracer blood sample data, it was found that normalized MRI-based AIFs could be successfully converted into PET tracer AIFs in the first pass phase when fitted with gamma variate functions. Finally, a MR image segmentation method used to provide PET attenuation correction in mice was validated using the Cambridge split magnet PET/MR scanner?s transmission scanning capabilities. This work recommends that contributions from MR hardware in the PET field of view must be accounted forto gain accurate estimates of tracer uptake and standard uptake values (SUVs). This thesis concludes that small animal MR data taken in the same imaging session can provide non-invasive methods to improve PET image quantification, giving added value to combined PET/MR studies over those conducted using PET alone.

Pulmonary artery hypertension (PAH) is a disease of progressive pulmonary vascular remodelling characterised by dysregulated proliferation and inflammation. With increasing acceptance that glucose metabolism is perturbed in proliferating and inflammatory cells in PAH, the present thesis took interest in the application of molecular 18F-2-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) imaging, widely used in the oncology clinic, in the assessment of PAH patients. Our hypothesis is that FDG-PET imaging can be used as a potential tool for the in vivo assessment of pulmonary vascular remodelling and evaluation of anti-remodelling therapies in PAH. In the first part of the thesis, a clinical applicable dynamic FDG-PET acquisition protocol with kinetic Patlak analysis was assessed in idiopathic PAH (IPAH) patients and PAH associated with systemic lupus erythematosus (SLE-PAH) patients for detection and quantification of lung FDG uptake. Mean lung FDG uptake was increased in both IPAH and SLE-PAH patients compared to that in healthy controls. There was heterogeneity of lung FDG uptake within PAH population, which aligns with our current understanding of the complex and regional pathology in PAH. Lung FDG uptake of SLE-PAH patients significantly correlated with SLE disease activity markers. In the following in vivo FDG-PET study, treatments with liraglutide and tacrolimus significantly attenuated the increased pulmonary artery pressure and right heart hypertrophy, as well as pulmonary vascular muscularisation and inflammatory cell infiltration in monocrotaline-induced PAH rat models, accompanied by a decreased lung FDG uptake. These data support further evaluation of the use of FDG-PET as a potential tool for evaluating these therapies in clinical trials. We learnt that FDG-PET imaging lacks specificity to differentiate proliferation from inflammation as an underlying disease process. Future development of other PET tracer may help to identify a marker that interrogates the pulmonary pathology of interest.

¹⁸F-FDG PET can predict response using both qualitative and quantitative measures. PET Therapy Response Assessor (PETTRA) software was developed to allow users to view and analyse pre- and post- therapy images and compute quantitative measures for predicting response to therapy. Additionally, registration methodology was developed to register pre- and post- therapy PET/CT images. The methodology registers pre- and post- therapy PET/CT scans by registering CT scans using customised rigid and non-rigid registration performed by the Image Registration Toolkit (IRTK). Registration success was assessed using qualitative visual analysis and quantitative landmark analysis on a cohort of 20 lymphoma patients. Landmark analysis results found average misalignment on IRTK of ~10mm for rigid registration and ~6.5mm for non-rigid registration, in comparison with ~40mm with no registration applied. The effect of both rigid and non-rigid registration on transformed images was assessed. While rigid registration transformation caused minimal changes on intensity and tumour volume (<2%), non-rigid transformations caused changes of 11% and 21% respectively. PETTRA software was used to analyse quantitative parameters in 14 patients with mesothelioma and 85 patients with diffuse large B-cell lymphoma (DLBCL). For the 14 patients with mesothelioma, a range of parameters were used to assess response including SUVmax, SUVpeak, tumour volume (TV), total lesion glycolysis (TLG) and intensity volume histogram (IVH) parameters. TV and TLG were obtained using 13 fixed and 9 adapative threshold segmentation methods. Pre-and post- therapy SUVmax, SUVpeak, TV and TLG all showed promise in predicting survival. The comparison between TV and TLG obtained using different segmentation methods was negligible. For the 85 patients with DLBCL, SUVmax, TV and TLG struggled to predict response in patients according to ROC curves.

The development of hybrid PET/MRI imaging systems needs to be paralleled with the development of a hybrid intrinsic PET/MRI probes. The aim of this work was to develop and validate a novel radio-superparamagnetic nanoparticle (r-SPNP) for hybrid PET/MRI imaging. This was achieved with the synthesis of superparamagnetic iron oxide nanoparticles (SPIONs) that intrinsically incorporated 59Fe and manganese iron oxide nanoparticles (MIONs) that intrinsically incorporated 52Mn. Both [59Fe]-SPIONs and [52Mn]-MIONs were produced through thermal decomposition synthesis. The physiochemical characteristics of the r-SPNPs were assessed with TEM, DLS, and zeta-potential measurements, as well as in imaging phantom studies. The [59Fe]-SPIONs were evaluated in vivo with biodistribution and MR imaging studies. The biodistrubution studies of [59Fe]-SPIONs showed uptake in the liver. This corresponded with major MR signal contrast measured in the liver. 52Mn was produced on natural chromium through the 52Cr(p,n)52Mn reaction. The manganese radionuclides were separated from the target material through a liquid-liquid extraction. The αVβ3 integrin binding of [52Mn]-MION-cRGDs was evaluated with αVβ3 integrin solid phase assays, and the expression of αVβ3 integrin in U87MG xenograft tumors was characterized with fluorescence flow cytometry. [52Mn]-MION-cRGDs were used for in vivo PET and MR imaging of U87MG xenograft tumor bearing mice. PET data showed increased [52Mn]-MION-cRGD uptake compared with untargeted [52Mn]-MIONs. ROI analysis of PET and MRI data showed that MR contrasted corresponded with PET signal. Future work will utilize [52Mn]-MION-cRGDs in other tumor models and with hybrid PET/MRI imaging systems.

Positron emission tomography is an imaging technique that appeared to be a valid instrument for cancers detection and neuro-imaging studies. Since first models built during 1960s, an incredible effort has been done by researchers to develop scanners more and more advanced with higher specificity and efficiency. Monte Carlo simulations have shown to be a very important tool during design phase of PET prototypes thanks to their ability to simulate systems with many coupled degrees of freedom, as it happens when particles interact with matter. This Thesis work has started in the frame the Crystal Clear Collaboration when the EndoTOFPET scanner was already under development. This prototype is an high spatial resolution scanner for the study of pancreatic carcinoma and prostatic cancer, composed by a PET head mounted on an ultrasound endoscope and a PET plate to be placed outside the body. The Collaboration has chosen to use Monte Carlo simulations to support the design of this project and two simulations toolkits were available: Geant4 and SLitrani. In this work both the toolkits are studied and ray tracing in scintillator crystals are tested. In particular photon extraction efficiency is simulated under different surface treatments as coating and wrapping. Also the influence of the crystals geometry on light output is tested simulating different scintillators sections and lengths. Both Geant4 and SLitrani have shown to give similar results under these conditions. A main issue was observed regarding secondary particles since Geant4 is able to simulate their production while it is not possible with SLitrani. On other hand crystals anisotropy for optical photons can be activated in SLitrani. Light yield measurements were performed in laboratory on LYSO and PbWO 4 crystals to have a comparison with the results obtained by mean of simulations. Good agreements are obtained for what regards surfaces treatments while more tuning was required to simulate the effect of surface imperfections and diffusion inside crystals. For the Collaboration purposes, Geant4 results more reliable and it allows to use GATE, an open source software specifically developed for the simulation of medical imaging scanners. Due to the peculiar structure of the PET prototype it was necessary to develop a code to simulate the electronic chain, responsible for transforming the gammas detected in usable data for image reconstruction. Different coincidences sorting algorithms were studied and methods to introduce instrumental uncertainties in data were developed and reported in this work. Simulations of EndoTOFPET scanner with different scintillator dimensions, modules geometries and plate configurations were performed. Sensibility and spatial resolution were used as elements of comparison and results collected by simulations are reported and analysed in this work. Time of flight was tested applying different time resolutions while system response to DOI analysis was studied too. Thanks to these first simulations, valuable information for the developing of this prototype were collected.

Introduction The 80kD glycoprotein transferrin (TF) and its related receptor (TFR1) play a major role in the recruitment by cancer cells of factors for their multiplication, adhesion, invasion and metastatic potential. Though primarily designed to bind iron and then be internalised into cells with its receptor, TF can also bind most transition metals such as Co, Cr, Mn, Zr, Ni, Cu, V, In & Ga. Under certain conditions TF binds Ti (IV) even more tightly than it does Fe and that this occurs at the N-lobe (as distinct from C) of apoTF. Further, under physiological conditions the species Fe(C)Ti(N)-TF may provide the route for Ti entry into cells via TFR1 (1). Thus, the radiometal PET reporter isotope 45Ti with an ‘intermediate’ (~hrs) half-life suited to tracking cell-focused biological mechanisms is an attractive option for elucidating cellular mechanisms involving TF binding and internalisation, at least in (preclinical) animal models. 45Ti (T½ = 3.08 hr; + branching ratio = 85 %; mean β+ energy = 439keV, no significant dose-conferring non-511keV γ-emissions) was produced using the reaction 45Sc(p,n)45Ti by irradiating (monoisotopic) scandium discs with an energy-degraded proton beam produced by an 18MeV isochronous medical cyclotron. Separation and purification was achieved with an hydroxylamine hydrochloride functionalised resin. Comparative microPET imaging was performed in an immunodeficient mouse model, measuring biodistributions of the radiolabels 45Ti-oxalate and 45Ti-human-TF (45Ti-h-TF), out to 6hr post-injection. Materials and Methods High purity 15mm diameter scandium disc foils (99.5%, Goodfellow, UK) each thickness 0.100 ± 0.005 mm (55 mg) were loaded into an in-house constructed solid-targetry system mounted on a 300mm external beam line utilising helium-gas and chilled water to cool the target body (2). The proton beam was degraded to 11.7 MeV using a graphite disc integrated into the graphite collimator. This energy abolishes the competing ‘contaminant’ reactions 45Sc(p,n+p)44Sc and 45Sc(p,2n)44Ti. Beam current was measured using the well documented 65Cu(p,n)65Zn reaction. Calculations showed that the chosen energy is close to the optimal primary energy (~12 MeV) for maximising the (thin-target) yield from a 0.100 mm thick target. For separation of Ti from the Sc target two methods were examined; (i) ion exchange column separation using 2000 mg AG 50W-X8 resin conditioned with 10mL 9M HCl. Disc is dissolved in 1 mL of 9M HCl, which at completion of reaction is pipetted into column. Successive 1 mL volumes of 9M HCl are added, and subsequent elutions collected. (ii) Following Gagnon et al., (3) a method employing hydroxylamine hydro-chloride functionalised resin (’hydroxamate method’) was applied, similar to its use in our hands for purification and separation of 89Zr (2) following its original description for 89Zr by Holland et al., (4). Disc dissolved in 2mL 6M HCl, then diluted to 2M. Elute through column to waste fraction 1 (w1 – see FIG. 1). Then elute 6 mL of 2M HCl through column to w2, followed by 6 mL of traceSELECT H2O to w3. Finally, elute Ti into successive 1 mL product fractions (p1, 2 etc.) using 5 mL of 1M oxalic acid. This procedure takes approximate 1 hr. 45Ti in elution vials was measured using γ-spectroscopy. Sc in the same vials was determined later using ICP-MS. Results A typical production run using a beam current of 40 μA for 60min on a 0.100mm-thick disc produced an activity of 1.83 GBq. Radionuclidic analysis of an irradiated disc using calibrated cryo-HPGe γ-spectroscopy revealed T½ = 2.97–3.19 hr (95% CI) for 45Ti, and with contaminant 44Sc < 0.19 %, with no other isotopes detected. Despite systematic adjustments to column conditions satisfactory chemical separation was not achieved using the ion exchange column method (i), despite previous reports of its success (5). Typical results of separation using the successful hydroxamate method (ii) are shown on the FIGURE 1. It is seen that significant portion of 45Ti is lost in the initial washing steps leading to waste collection. N = 4 replicate experiments showed a variation (SD) of 10 % of the mean in each elu-tion fraction. Subsequent ICP-MS of the same elutions for (cold) Sc showed approximately 80 % by mass appeared in w1 and 20 % in w2, with negligible total mass (total fraction ~1/6000) of Sc in product (p1–4) vials. However, the FIG. 1 shows that a total of only 30% of the original activity of 45Ti (corrected to EOB) is available in the product vials, with the vial of highest specific activity (p1) containing 14 %. However, using a stack of 2×0.100mm thick Sc discs as a target yields isotope of adequate specific activity with-out need for concentration, for subsequent labelling and small-animal imaging purposes. In a ‘proof-of-principle’ experiment, two groups of healthy Balb/c-nu/nu female adult mice were administered with 45Ti radiotracers. The first group (N = 3) received approximately 20 MBq IP of 45Ti-oxalate buffered to pH = 7.0, and under-went microPET/CT imaging (Super Argus PET, Sedecal, Spain) out to 6hr post-injection, plus biodistribution analysis of radioactivity by dis-section at sacrifice (6hr). The second group (N = 3) received approximately 20 MBq IP of 45Ti-h-TF and were also studied to 6hr post-injection, followed by radioactive analysis after dissection at sacrifice. Organ and tissue biodistributions of the two groups at 6hr were similar but with 45Ti-oxalate showing slightly greater affinity for bone. Biodistribution by dissection results broadly confirmed the findings from PET images. However, TLC results suggested that similarity of radiolabel biodistributions of the two groups may be due to contamination of the TF radiolabel with non-conjugated Ti at time of injection. An alternative explanation is dechelation in vivo of 45Ti from 45Ti-h-TF. Conclusion Despite significant loss of 45Ti to the waste fractions of the separation process (total 53 %, corrected to EOB), 45Ti of acceptable specific activity and high radionuclidic purity has been produced from the reaction 45Sc(p,n)45Ti, with separation and purification of the product by hydroxamate column chemistry, confirming an earlier report. Though microPET in vivo imaging using 45Ti-based radiolabels was shown to be feasible, the similarity in the results for the label 45Ti-h-TF compared with ‘raw’ 45Ti-oxalate suggests further investigations. These may include a direct comparison of in vivo 45Ti-h-TF small-animal imaging plus post-dissection biodistribution with the same procedures using 89Zr labelled h-apotransferrin (6).

Le tecniche di imaging molecolare permettono di visualizzare e caratterizzare processi biologici e rivestono un ruolo fondamentale in oncologia, consentendo di identificare marcatori per la diagnosi e la risposta al trattamento. In questo lavoro di tesi è stato valutato il ruolo della PET come possibile marcatore di risposta al trattamento in a) un modello con k-ras oncogenico e b) un modello di glioma, focalizzando l’attenzione sulle alterazioni del metabolismo e l’ipossia. L’incremento della glicolisi e del consumo di glutammina sono associati a mutazioni dell’oncogene ras in diversi tumori. Il disaccoppiamento di tali processi determina una riprogrammazione del metabolismo per supportare l’aumentata proliferazione fornendo un interessante target terapeutico. Scopo dello studio è la valutazione in vivo delle alterazioni metaboliche e della risposta alla terapia nel modello ottenuto mediante inoculo di fibroblasti con k-ras oncogenico (NIH-RAS). A tale scopo gruppi di topi sono stati monitorati longitudinalmente mediante PET-[18F]FDG e [18F]FLT per la valutazione del metabolismo glucidico e della proliferazione cellulare. I tumori sono stati sottoposti ad analisi immunoistochimiche per confermare i dati ottenuti in vivo. Nello stesso modello è stato valutato l’effetto di un inibitore dell’autofagia (Clorochina) e della glutaminasi (BPTES) singolarmente e in combinazione mediante PET-[18F]FDG e [18F]FLT. Gli animali hanno sviluppato in breve tempo tumori glicolitici e caratterizzati da un’omogenea captazione di [18F]FDG e [18F]FLT. Le immagini PET hanno mostrato un aumento della captazione di [18F]FDG nel tempo e un andamento stabile della proliferazione come mostrato dalla costante captazione di [18F]FLT. Clorochina e BPTES in combinazione hanno determinato un rallentamento della crescita tumorale rispetto ai controlli, ma non sono state osservate variazioni nella captazione di [18F]FDG e [18F]FLT. La presenza di vie alternative per la produzione di glutammato e la necessità di dosi più elevate potrebbero spiegare l’assenza di efficacia di questi trattamenti. L’ipossia rappresenta un fenomeno sfavorevole per la progressione tumorale. L’espressione di HIF1α, principale regolatore dell’ipossia, è associata alla resistenza alla terapia in molti tumori, compreso il glioma. Per questo, una migliore comprensione della modulazione dell’attività di HIF1α nel processo di risposta alla terapia è di particolare interesse. Cellule di glioma U251-HRE-mCherry in grado di esprimere l’enzima luciferasi sotto il controllo di HRE (Hypoxia Responsive Element) e mCherry sotto controllo di un promotore costitutivo sono state utilizzate per valutare la modulazione di HIF1α in seguito a trattamento con Temozolomide (TMZ) in vitro e in vivo. La crescita tumorale è stata monitorata in vivo in animali sottoposti ad inoculo intracerebrale tramite bioluminescenza, fluorescenza, RM e PET con [18F]FAZA e [18F]FLT. In seguito, è stato valutato in vivo l’effetto di due diversi regimi di TMZ. Mediante bioluminescenza è stato possibile monitorare la crescita tumorale e identificare aree ipossiche. I dati ottenuti sono stati confermati dalle immagini di fluorescenza e PET-[18F]FAZA. Le analisi ex vivo per Ki67 hanno invece confermato i dati PET-[18F]FLT ed hanno mostrato un’elevata proliferazione cellulare. Entrambi i dosaggi di TMZ hanno determinato una diminuzione dell’attività di HIF1α a tempi precoci. Al contrario, il segnale di fluorescenza e la captazione di [18F]FLT hanno subìto una diminuzione solo a tempi più tardivi. L’attività di HIF1α può essere considerata un marcatore di risposta al TMZ e questo modello un utile strumento per la valutazione in vivo di farmaci per il trattamento del glioma.
Molecular imaging allows the non-invasive visualization and characterization of biological processes. It can be used in oncology to identify biomarkers for the evaluation of tumor progression and response to therapy. In this thesis work, the animal PET was used as potential biomarker of tumor response to therapy focusing on altered metabolism and hypoxia in a) a model of oncogenic k-ras and b) in a model of glioma. Metabolic alterations, such as increased glycolysis and glutamine consumption, are associated with mutations in k-ras gene. The decoupling of glucose and glutamine uptake leads to a reprogramming of their metabolism to support cell proliferation representing a target for cancer therapy. The aim of this study is to investigate metabolic alterations in k-ras transformed fibroblasts (NIH-RAS) in in vivo studies and to assess response to therapy. Animals subcutaneously implanted with NIH-RAS performed [18F]FDG- and [18F]FLT-PET at several time points to evaluate glucose metabolism and cell proliferation, respectively. Tumors were collected and evaluated for different markers by immunohistochemistry (IHC) to confirm in vivo results. In the same model, the efficacy of chloroquine (autophagy blocker) and BPTES (glutaminase inhibitor) alone or in combination was monitored by [18F]FDG- and [18F]FLT-PET before and 48 hours after treatments. All animals developed fast growing and highly glycolytic tumors in few days that appear homogeneous for both [18F]FDG and [18F]FLT uptake. PET imaging showed a significant increase in [18F]FDG uptake while cell proliferation remained stable over time, as depicted by [18F]FLT uptake. IHC analyses confirmed the high aggressiveness of these cells. Chloroquine and BPTES combined treatment slowed down tumor growth only if compared to vehicle, without affecting glucose metabolism or cell proliferation. The presence of alternative pathways for glutamate production and the need of higher doses of treatments may provide explanations to the lack of treatments’ efficacy. Hypoxia is implicated in many aspects of tumor progression and it is involved in the intracellular stabilization of the hypoxia regulator gene HIF-1α. Since the expression of HIF-1α is associated with poor prognosis and therapy resistance in glioblastoma, a better comprehension of its involvement in tumor response to treatment can be of great interest for clinical translation. U251-HRE-mCherry cells expressing Luciferase under control of a Hypoxia Responsive Element (HRE) and mCherry under the control of a constitutive promoter have been used to assess HIF-1α modulation and cell survival after treatment, both in vitro and in vivo. In vivo analyses characterized the model obtained by stereotaxic injection of glioma U251-HRE cells in mice brain. Tumor progression was monitored comparing bioluminescence, fluorescence and PET with [18F]FAZA and [18F]FLT. Afterwards, two regimens of temozolomide (TMZ) were administered starting 21 days after cells injection. TMZ efficacy was monitored by optical and fluorescence imaging, [18F]FLT-PET and MRI. Bioluminescent signals provided information about tumor growth and hypoxia presence, confirmed by both fluorescence acquisition and [18F]FAZA PET. IHC for Ki67 confirmed data obtained by [18F]FLT-PET, showing a high rate of cell proliferation. Both TMZ regimens showed a decrease of HIF-1α-dependent Luciferase activity at early time after TMZ administration. On the contrary, mCherry fluorescence, such as [18F]FLT uptake, decreased only at the end of treatments. HIF-1α activity reduction can be considered a biomarker of tumour response to TMZ and the U251-HRE-mCherry cell model a feasible tool to evaluate HIF-1α activity and treatment effects in in vivo studies.

Cardiovascular disease remains the commonest cause of death worldwide. The majority of deaths are caused by atherosclerotic plaque rupture with resultant myocardial infarction or stroke, or rupture of abdominal aortic aneurysms. Conventional imaging modalities have consistently failed to identify atherosclerotic plaques or aneurysms with high-risk pathological features that are at highest risk of rupture or progression. The development of modern molecular imaging techniques targeted at these features could lead to the identification of such high-risk plaques and aneurysms in vivo and guide the development of novel treatment strategies. The aim of this thesis was to evaluate whether novel molecular modalities have a role in providing new insights into biological disease processes, and identify high-risk plaques and aneurysms. Using positron emission tomography-computed tomography (PET-CT), 18F-fluorodeoxyglucose and 18F-fluoride were utilised as markers of metabolic inflammation and active calcification. Cellular inflammation was assessed using ultrasmall superparamagnetic particles of iron oxide (USPIO) enhanced magnetic resonance imaging (MRI). In a prospective trial, 80 patients with myocardial infarction (n=40) and stable angina (n=40) underwent 18F-fluoride and 18F-fluorodeoxyglucose PET-CT, and invasive coronary angiography (Chapter 3). Intense 18F-fluoride uptake localised to recently ruptured plaque in patients with acute myocardial infarction. In patients with stable coronary artery disease, 18F-fluoride uptake identified coronary plaques with high-risk features on intravascular ultrasound. 18F-fluoride PET-CT is the first noninvasive imaging method to identify and localise ruptured and high-risk coronary plaques. Aortic vascular uptake of 18F- fluorodeoxyglucose was studied in patients with myocardial infarction and stable angina (Chapter 4). In a separate outcome of 1,003 patients enrolled in the Global Registry of Acute Coronary Events, we further evaluated whether infarct size predicted recurrent coronary events. Patients with myocardial infarction had higher remote atherosclerotic tracer uptake that correlated with the degree of myocardial necrosis, and exceeded that observed in patients with stable coronary disease. The outcome cohort demonstrated that patients with higher degree of myocardial necrosis had the highest risk of early recurrent myocardial infarction. This supports the hypothesis that acute myocardial infarction exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: myocardial infarction begets myocardial infarction. In a prospective imaging cohort, the role inflammation and calcification was assessed in 63 patients with abdominal aortic aneurysms and 19 age and sex matched patients with atherosclerosis (Chapter 5). Compared to non-aneurysmal segments, enhanced inflammation and calcification was observed within the wall of aortic aneurysmal segments. In comparison to matched controls with atherosclerosis, the entire aorta in those with aortic aneurysm appears more highly inflamed, suggesting presence of a global aortopathy rather than a disease confined only to the abdominal region of the aorta. Aortic aneurysms have greater active inflammation and calcification than atherosclerotic controls suggesting a more intense, destructive and transmural pathological process. A subgroup of fifteen patients with aortic aneurysms underwent imaging with both PET-CT with 18F-fluorodeoxyglucose, and T2*- weighted MRI before and 24 h after administration of USPIO (Chapter 6). Whilst there was a moderate correlation between the two tracers, there were distinct differences in the pattern and distribution of uptake suggesting a differential detection of macrophage glycolytic and phagocytic activity respectively. These studies provide novel insights into vascular biological processes involved in the initiation, progression and rupture of atherosclerotic plaques and aortic aneurysms. Future longitudinal studies are needed to establish whether these techniques have a role in improving the clinical management and treatment of patients with coronary artery disease and aortic aneurysms.

Thesis (M.A.)--Boston University
The standardized uptake value (SUV) is increasingly being used for diagnosis, staging, and monitoring disease in clinical oncology. Comparing tumor SUV to background SUV is an attractive way to minimize variability and ensure the quality of scans across different institutions. The liver has been identified as a potential source for background normalization, however no studies have compared the liver to other background sites for a variety of cancers. The purpose of this study was to evaluate the use of liver uptake for the standardization of FDG PET/CT imaging. Scans from 145 patients were prospectively reviewed under the supervision of a radiologist with board certification in nuclear medicine (R.M.S. , 3 years of experience). Liver SUV values were correlated to mediastinum SUV values in lung and breast cancer patients, and internal jugular vein (IJV) SUV values in head and neck cancer patients. The independent t-test was used to determine if there was a statistically significant affect of the amount of incubation time or use of intravenous contrast on the SUV. For the lung and breast cancer patients, a strong correlation was observed between the mediastinum SUVmean and liver SUVmean (r = 0.89), whereas for the head and neck cancer patients, a weaker correlation was observed between the IJV SUVmean and the liver SUVmean (r = 0.69). Neither the amount of incubation time nor the use of IV contrast demonstrated a significant affect on the SUV. We conclude that liver SUVmean may be used to standardize FOG PET/CT studies in cancers of the lung, breast and head and neck. However, additional studies in other cancers as well as the affects of age, gender, benign disease and use of chemotherapy are still desired before widespread adoption of this standard.

Introduction: Low-grade gliomas are a sub-group of primary brain tumours that typically affect young adults and which present specific challenges to conventional diagnostic imaging. They demonstrate a pattern of growth whereby tumour cells infiltrate healthy brain tissue without distortion of the surrounding brain or blood-brain barrier integrity. These features limit the capacity of conventional neuro-imaging strategies to effectively delineate the tumour extent or characterise the degree of 'malignancy'. One solution is to apply multiple imaging modalities to image different aspects of the tumour behaviour, analogous to histological classification based upon changes in mitotic activity, cellular atypia, microvascular proliferation and necrosis. Published information regarding how imaging techniques that address these parameters correlate within the tumour volume is limited. This reflects the technical challenges in acquiring and processing data at an adequate spatial resolution to characterise small but heterogenous tumours. In this thesis, following a series of experiments seeking to optimise the sensitivity and reproducibility of PET analysis in gliomas, a prospective multi-modal neuro-imaging study is presented addressing this need. Methods: Retrospective [11C]-methionine PET (MET PET) data made available through a collaboration with the Max-Planck Institute for Neurological Research in Cologne was carried out first to address the optimal method of analysis of PET data in gliomas. A normal methionine uptake map was created and its use in the analysis of patient scans validated against a conventional approach. Automated methods for delineating the extent of abnormal methionine uptake and identifying the region of peak uptake were developed and evaluated to optimise the reproducibility of the approach. High-resolution MET PET and a comprehensive MRI brain tumour protocol were then acquired prospectively in 20 subjects in Manchester. Detailed analysis of the peak uptake and extent of abnormal tissue defined using PET and MRI modalities including structural, diffusion- and perfusion-weighted techniques was performed. Results: Evaluation of methionine uptake with respect to population normal data, the 'RatioMap' technique, yielded peak uptake measurements that correlated closely with a conventional approach (r = 0.97) but with improved reproducibility. The constrained 3D region-growing algorithm designed to delineate the abnormal region was shown to be reproducible and to generate volumes that correlated with tumour grade. High-resolution multi-modal data in suspected low-grade gliomas demonstrated consistent correlation between peak methionine uptake ratio and peak regional cerebral blood volume (r = 0.85) but with disparity between the location of the maximal uptake regions (mean distance = 11.2mm). Significant correlation was seen between multi-modal MRI and PET ‘tumour’ volumes (r = 0.91) but with substantially larger MRI defined abnormal volumes (ratio = 2.0) including small regions identified as abnormal by multiple MRI parameters but normal on PET imaging. Conclusion: A novel method to enhance the reproducibility of analysis of MET PET images in gliomas has been presented and validated but there remains no single imaging modality capable of fully characterising glioma extent and 'malignancy' non-invasively. Considerable correlation between PET and MRI tumour biomarkers has been demonstrated but there are significant differences between the regions identified as the 'most malignant' for biopsy targeting and the extent of potentially tumour bearing tissue. Combined use of diffusion- and perfusion-weighted MRI parameters can provide results very closely correlated to the PET findings but cannot yet completely replace the use of nuclear medicine techniques. The use of multi-modal approaches to tumour characterisation as demonstrated in this study provides the most effective currently available approach to fully characterise a suspected glioma.

Dementia is a chronic neurodegenerative disease impacting millions of elderlies globally every single day. There are several well-known forms of dementia. Alzheimer’s Disease (AD) is the most prevalent and deadly with no known cure. However, there are effective interventions to delay onset of AD only if it is detected early. Fludeoxyglucose/Pittsburgh compound B Positron Emission Tomography (FDG/PiB PET) is one of the most effective medical imaging modalities used by doctors for early AD identification for prospective patients. The task of diagnosing AD by visually examining PET images, however, is usually time consuming and highly depends on the experience of the examiners. Another challenge related to this task is the potential loss of valuable information contained in past PET scans once they are archived post-diagnosis. There is a need for computer-aided early AD identification systems to assist doctors in clinical environment by providing useful second opinion. However, building such systems are extremely challenging due to three main reasons. Firstly, the poor resolution of brain scans acquired from PET scanner makes extracting salient spatial features from these scans a challenging task. Secondly, in PET images obtained from clinical environment are usually poorly labelled due to the fact that Alzheimer’s disease cannot be confirmed until a series of follow-up scans over a long period of time are examined or after post-mortem. This prevents supervised machine learning models from being trained properly. At last, longitudinal PET images are usually difficult to obtain due to subject drop-off during follow-up period. These data provide extremely valuable insights into the development of dementia. And understanding how dementia progresses for different subject will greatly benefit the development of personalised dementia care. In this thesis, we focus on solving these key issues by proposing several different machine learning-based methods. To select the salient feature variables from PET images, we propose a novel feature selection algorithm inspired by evolutionary computing. We also propose a method for simultaneous feature selection and Alzheimer’s disease classification, and we show the consistency between the selected features and clinically verified knowledge. To solve the PET image quality issue, we propose a novel kernel learning method under the Robust Programming framework. We then focus on the challenging data issues existing in clinical environment and propose two different but related semi-supervised learning methods. At last, we design and implement a pipeline for dementia progression direction prediction using longitudinal PET images. The pipeline contains a sequence recovery component to recover missing observations and a sequence recognition component for temporal pattern recognition. The significance of our study is that it shows doctors the usefulness of the second opinion for early AD detection in several different practical scenarios, provided by efficient and effective machine learning models built on PET imaging data.

[ES] La Tomografía por Emisión de Positrones (PET) es una de las técnicas más importantes en la medicina de diagnóstico actual y la más representativa en el campo de la Imagen Molecular. Esta modalidad de imagen es capaz de producir información funcional única, que permite la visualización en detalle, cuantificación y conocimiento de una variedad de enfermedades y patologías. Áreas como la oncología, neurología o la cardiología, entre otras, se han beneficiado en gran medida de esta técnica. A pesar de que un elevado número de avances han ocurrido durante el desarrollo del PET, existen otros que son de gran interés para futuras investigaciones. Uno de los principales pilares actualmente en PET, tanto en investigación como en desarrollo, es la obtención de la información del tiempo de vuelo (TOF) de los rayos gamma detectados. Cuando esto ocurre, aumenta la sensibilidad efectiva del PET, mejorando la calidad señal-ruido de las imágenes. Sin embargo, la obtención precisa de la marca temporal de los rayos gamma es un reto que requiere, además de técnicas y métodos específicos, compromisos entre coste y rendimiento. Una de las características que siempre se ve afectada es la resolución espacial. Como discutiremos, la resolución espacial está directamente relacionada con el tipo de centellador y, por lo tanto, con el coste del sistema y su complejidad. En esta tesis, motivada por los conocidos beneficios en imagen clínica de una medida precisa del tiempo y de la posición de los rayos gamma, proponemos configuraciones de detectores TOF- PET novedosos capaces de proveer de ambas características. Sugerimos el uso de lo que se conoce como métodos de "light-sharing", tanto basado en cristales monolíticos como pixelados de tamaño diferente al del fotosensor. Estas propuestas hacen que la resolución espacial sea muy alta. Sin embargo, sus capacidades temporales han sido muy poco abordadas hasta ahora. En esta tesis, a través de varios artículos revisados, pretendemos mostrar los retos encontrados en esta dirección, proponer determinadas configuraciones y, además, indagar en los límites temporales de éstas. Hemos puesto un gran énfasis en estudiar y analizar las distribuciones de la luz centellante, así como su impacto en la determinación temporal. Hasta nuestro conocimiento, este es el primer trabajo en el que se estudia la relación de la determinación temporal y la distribución de luz de centelleo, en particular usando SiPM analógicos y ASICs. Esperamos que esta tesis motive y permita otros muchos trabajos orientados en nuevos diseños, útiles para instrumentación PET, así como referencia para otros trabajos. Esta tesis esta organizada como se describe a continuación. Hay una introducción compuesta por tres capítulos donde se resumen los conocimientos sobre imagen PET, y especialmente aquellos relacionados con la técnica TOF-PET. Algunos trabajos recientes, pero aún no publicados se muestran también, con el objetivo de corroborar ciertas ideas. En la segunda parte se incluyen las cuatro contribuciones que el candidato sugiere para el compendio de artículos.
[CA] La Tomografia per Emissió de Positrons (PET) és una de les tècniques més importants en la medicina de diagnòstic actual i la més representativa en el camp de la Imatge Molecular. Esta modalitat d'imatge és capaç de produir informació funcional única, que permet la visualització en detall, quantificació i coneixement d'una varietat de malalties i patologies. Àrees com l'oncologia, neurologia o la cardiologia, entre altres, s'han beneficiat en gran manera d'aquesta tècnica. Tot i que un elevat nombre d'avanços han ocorregut durant el desenvolupament del PET, hi ha altres que són de gran interés per a futures investigacions. Un dels principals pilars actuals en PET, tant en investigació com en desenvolupament, és l'obtenció de la informació del temps de vol (TOF en anglès) dels raigs gamma detectats. Quan açò ocorre, augmenta la sensibilitat efectiva del PET, millorant la qualitat senyal-soroll de les imatges. No obstant això, l'obtenció precisa de la marca temporal dels raigs gamma és un repte que requerix, a més de tècniques i mètodes específics, compromisos entre cost i rendiment. Una de les característiques que sempre es veu afectada és la resolució espacial. Com discutirem, la resolució espacial està directament relacionada amb el tipus de centellador, i per tant, amb el cost del sistema i la seua complexitat. En aquesta tesi, motivada pels coneguts beneficis en imatge clínica d'una mesura precisa del temps i de la posició dels raigs gamma, proposem nouves configuracions de detectors TOF-PET capaços de proveir d'ambduess característiques. Suggerim l'ús del que es coneix com a mètodes de "light-sharing", tant basat en cristalls monolítics com pixelats de diferent tamany del fotosensor. Aquestes propostes fan que la resolució espacial siga molt alta. No obstant això, les seues capacitats temporals han sigut molt poc abordades fins ara. En aquesta tesi, a través de diversos articles revisats, pretenem mostrar els reptes trobats en aquesta direcció, proposar determinades configuracions i, a més, indagar en els límits temporals d'aquestes. Hem posat un gran èmfasi a estudiar i analitzar les distribucions de la llum centellejant, així com el seu impacte en la determinació temporal. Fins al nostre coneixement, aquest és el primer treball en què s'estudia la relació de la determinació temporal i la distribució de llum de centelleig, en particular utilitzant SiPM analògics i ASICs. Esperem que aquesta tesi motive i permeta molts altres treballs orientats en nous dissenys, útils per a instrumentació PET, així com referència per a altres treballs. Aquesta tesi esta organitzada com es descriu a continuació. Hi ha una introducció composta per tres capítols on es resumeixen els coneixements sobre imatge PET i, especialmente, aquells relacionats amb la tècnica TOF-PET. Alguns treballs recents, però encara no publicats es mostren també, amb l'objectiu de corroborar certes idees. La segona part de la tesi conté els quatre articles revisats que el candidat suggereix.
[EN] Positron Emission Tomography (PET) is one of the greatest tools of modern diagnostic medicine and the most representative in the field of molecular imaging. This imaging modality, is capable of providing a unique type of functional information which permits a deep visualization, quantification and understanding of a variety of diseases and pathologies. Areas like oncology, neurology, or cardiology, among others, have been well benefited by this technique. Although numerous important advances have already been achieved in PET, some other individual aspects still seem to have a great potential for further investigation. One of the main trends in modern PET research and development, is based in the extrapolation of the Time- Of-Flight (TOF) information from the gamma-ray detectors. In such case, an increase in the effective sensitivity of PET is accomplished, resulting in an improved image signal-to-noise ratio. However, the direction towards a precise decoding of the photons time arrival is a challenging task that requires, besides specific approaches and techniques, tradeoffs between cost and performance. A performance characteristic very habitually compromised in TOF-PET detector configurations is the spatial resolution. As it will be discussed, this feature is directly related to the scintillation materials and types, and consequently, with system cost and complexity. In this thesis, motivated by the well-known benefits in clinical imaging of a precise time and spatial resolution, we propose novel TOF-PET detector configurations capable of inferring both characteristics. Our suggestions are based in light sharing approaches, either using monolithic detectors or crystal arrays with different pixel-to-photosensor sizes. These approaches, make it possible to reach a precise impact position determination. However, their TOF capabilities have not yet been explored in depth. In the present thesis, through a series of peer-reviewed publications we attempt to demonstrate the challenges encountered in these kinds of configurations, propose specific approaches improving their performance and eventually reveal their limits in terms of timing. High emphasis is given in analyzing and studying the scintillation light distributions and their impact to the timing determination. To the best of our knowledge, this is one of the first works in which such detailed study of the relation between light distribution and timing capabilities is carried out, especially when using analog SiPMs and ASICs. Hopefully, this thesis will motivate and enable many other novel design concepts, useful in PET instrumentation as well as it will serve as a helpful reference for similar attempts. The present PhD thesis is organized as follows. There is an introduction part composed by three detailed sections. We attempt to summarize here some of the knowledge related to PET imaging and especially with the technique of TOF-PET. Some very recent but still unpublished results are also presented and included in this part, aiming to support statements and theories. The second part of this thesis lists the four peer-reviewed papers that the candidate is including.
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 695536). It has also been supported by the Spanish Ministerio de Economía, Industria y Competitividad under Grants No. FIS2014-62341-EXP and TEC2016-79884-C2-1-R. Efthymios Lamprou has also been supported by Generalitat Valenciana under grant agreement GRISOLIAP-2018-026.
Lamprou, E. (2021). Development and Performance Evaluation of High Resolution TOF-PET Detectors Suitable for Novel PET Scanners [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/162991
TESIS

Positron emission tomography (PET) is on the forefront of cancer diagnosis, clinical drug evaluation, and patient management. Among the numbers of β+-emitting nuclides, ¹⁸F (t₁/₂=109.8 min) is a mainstay isotope for PET imaging owing to its excellent nuclear properties and on-demand production at Curie levels. Despite the success of PET and increasing interests of ¹⁸F-radiochemistry, a facile ¹⁸F-labeling method that can be broadly applied to biomolecules has been a long-standing challenge. Most known ¹⁸F-labeling methods are relatively onerous and lengthy processes, which is a particularly serious problem given the short half-life of ¹⁸F. This thesis describes the design, synthesis and in vivo evaluation of novel ¹⁸F-radioprosthetics based on B-¹⁸F formation, and aims at developing a facile and broadly applicable ¹⁸F-labeling method for PET imaging. Previously, the Perrin group has established ¹⁸F-aryltrifluoroborates as a promising radiosynthon to radiolabel bioligands. In light of this success, this thesis has dedicated to expand B-¹⁸F labeling method from a scientific design to a generic clinical-friendly tool for developing new PET tracers. The first highlight of this thesis is to create new labeling methods (Chapter 4 and Chapter 5) to increase the specific activity of ¹⁸F-radiotracers to 15 Ci/μmol, which is about a magnitude higher than normal maximum. The second highlight is to discover a heretofore-unknown linear correlation between the solvolytic stability for a given organotrifluoroborate and the pKa of the corresponding carboxylic acids (Chapter 3). This discovery has fundamental interests for Suzuki-Miyaura coupling and also leads me to find a novel B-¹⁸F radiosynthon that combines high in vivo stability and “kit-like” ¹⁸F-labelling technology, which is the third highlight and also the core of this body of work (Chapter 6). Along with this, numbers of bioligands have been biologically evaluated, and some of them demonstrate excellent in vivo performance. Particularly, TATE-AMBF₃, which is an octreotate derivative, showing the best performance of any ligands for imaging somatostatin receptors in several decades (Chapter 7). In addition, for seamless bench-to-bed translation, a dual-modal strategy of synthesizing fluorescent PET tracer is presented (Chapter 8).
Science, Faculty of
Chemistry, Department of
Graduate

The thesis of this study describes a synthesis way to produce an alkyne equipped clickable precursor of 2-deoxy-2-fluoro-D-glucose (FDG) with a beta-configuration. This FDG-derivate is produced with a clickable link in purpose to be used in PET in vivo imaging. The product was synthesized by acetylation protection and further epoxidation on the glucose analog D-Glucal. Glycosylation occurred by electrophilic reaction of propargyl alcohol and configuration of the product was ensured during Lattrell-Dax inversion.

Traditionally, in Positron emission tomography (PET) scanners, the detection of simultaneous gamma ray emissions resulting from positron annihilations has been achieved using Photo-multiplier tubes (PMTs) optically coupled to dense scintillators. The recent development of the Avalanche photo-diode (APD) offers the possibility of replacing the PMT, however, such a step is not without its problems. The introduction of APD technology into scintillation detector design offers: more compact scanner design; the possibility of a multi-layer scintillation detector, with an inherent reduction in parallax errors; improved spatial, energy and timing resolutions; increased count-rate; and a higher packaging fraction with correspondingly increased scanner sensitivity. A well-designed APD-based scintillation detector can only be realised if all stages of the detection process are fully understood. The work described in this thesis shows that it is possible to model the complex processes of gamma ray interaction, scintillation, and light transport, using Monte Carlo methods; and to model the photo-detector output signal and its processing using both simplified circuit analysis and a standard circuit simulation software. These models were then combined to form a powerful modelling tool for APD-based scintillation detector design; this modelling tool was then used to design a multi-layer scintillation detector, which was built and tested. The performance of the detector closely matched the simulations. The measured performance parameters of the laboratory prototype were: intrinsic spatial resolution 2.0 mm (FWHM at 0.511 MeV), energy resolution 15% (FWHM at 0.511 MeV) and timing resolution of 2.2ns (FWHM), with a reconstructed image resolution of 1.6 mm (FWHM). THE prototype performance figures match any known commercially available Small animal PET scanner at this time.

PET image degradation imposed by patient respiratory motion is a well-established problem in clinical oncology; strategies exist to study and correct this. Some attempt to minimise or arrest patient motion through restraining hardware; their effectiveness is subject to the comfort and compliance. Another practice is to gate PET data based on signals acquired from an external device. This thesis presents several contributions to the field of respiratory motion correction research in PET imaging. First and foremost, this thesis presents a framework which allows a researcher to process list mode data from a Siemens Biograph mCT scanner and reconstruct sinograms of which in the open source image reconstruction package STIR. Secondly, it demonstrates the viability of a depth camera for respiratory monitoring and gating in a clinical environment. It was demonstrated that it was an effective device to capture anterior surface motion. Similarly, it has been shown that it can be used to perform respiratory gating. The third contribution is the design, implementation and validation of a novel respiring phantom. It has individually programmable degrees of freedom and was able to reproduce realistic respiration motion derived from real volunteers. The final contribution is a new gating algorithm which optimises the number and width of gates based on respiratory motion data and the distribution of radioactive counts. This new gating algorithm iterates on amplitude based gating, where gates as positioned based on respiratory pose at a given instant. The key improvement is that it considers the distribution of counts as a consequence of the distribution of motion in a typical PET study. The results show that different studies can be optimised with a unique number of gates based on the maximum extent of motion present and can take into account shifts in baseline position due to patient perturbation.

Positron emission tomography (PET) is a widely used molecular imaging modality,which offers quantitative information about many biochemical processes in vivo. In particular, the dynamic PET data provide physiologically meaningful parametricimages after the estimation of the parameters of a model that best describes thekinetic behaviour of the injected radiotracer. Spatiotemporal 4D image reconstructionalgorithms estimate these physiological parameters directly from the raw sinogramdata, where the noise distribution can be more accurately modelled and thus leading tostatistically more reliable parameter estimates. In this thesis a novel direct parametricimage reconstruction algorithm is introduced, which is based on the expectationmaximisation (EM) framework and is applicable to any spatiotemporal model. Themethod is evaluated for the spectral analysis model, which is a linear temporal modeland a two-tissue compartment model, which is a nonlinear temporal model. Inaddition, the method is evaluated for a linear spatial model and in particular the modelthat is normally used to describe the blurring components in image-based resolutionmodelling. Finally, the performance of gradient-based 3D reconstruction algorithmswas also assessed as an alternative to the well-established EM-based algorithms.