[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)

Resolving particle acceleration and transport in the jets of the microquasar SS 433 with H.E.S.S. and HAWC

The microquasar SS 433 offers a unique laboratory to study the physics of mildly relativistic jets and the associated non-thermal processes. It hosts a compact binary system, from which a pair of counter-propagating jets is observed to emanate. The jets are resolved by observations out to distances of approximately 0.1 pc from the central source, but further out, they remain dark until they abruptly reappear at around 25 pc as bright X-ray sources. These outer jets were recently reported to be sources of TeV gamma-rays by the High Altitude Water Cherenkov (HAWC) observatory. This thesis presents a complete picture of the TeV emission from the jets of SS 433 including new data from the High Energy Stereoscopic System (H.E.S.S.) and the HAWC observatory. To fully exploit the capabilities of the H.E.S.S. observations, a new approach to background rejection is presented. It is based on the detection of Cherenkov light from muons by large Imaging Atmospheric Cherenkov Telescopes (IACTs), such as the telescope located at the center of the H.E.S.S. array. The application of this technique leads to a factor four reduction in background above several tens of TeV in the H.E.S.S. stereoscopic analysis. This thesis presents the detection of the SS 433 outer jets for the first time with an IACT array using H.E.S.S.. The superior angular and energy resolution of H.E.S.S. compared to HAWC allow for a detailed study of the emission from the jets, including a measurement of the physical extension of the emission and of the spectra out to tens of TeV. These observations also reveal the presence of striking energy- dependent morphology, ruling out a hadronic origin for the bulk of the gamma-ray emission. Photons above 10 TeV are observed only close to the base of the outer jets, implying efficient particle acceleration to very-high energies at that location. Evidence suggests that the acceleration is due to a shock, thus providing a clue to the long-standing question of the reappearance of the jets. The observed energy-dependent morphology is modeled as a consequence of the particle cooling times and the advection flow of the jet, which constrains the jet dynamics and, in particular, results in an estimate of the velocity of the outer jets at their base. This solves several issues concerning the non-thermal processes occurring in the jets and their dynamics, but also opens up new questions that highlight our incomplete understanding of the SS 433 system. A joint analysis of the H.E.S.S. and HAWC data would provide insights on the system across the entire range of TeV energies. To make this possible, a tool capable of reading and analyzing the data from both instruments is required. This thesis presents the extension and validation of an existing data format and analysis tool shared among IACTs to the data from particle detector arrays such as the HAWC observatory. This framework is then used to revisit the HAWC observations of the SS 433 region with the inclusion of additional data taken since the first detection was reported. The existence of this framework enables for the first time the joint analysis of the H.E.S.S. and HAWC data, the preliminary results of which are presente

The experience in a Center of Excellence in Preclinical Imaging: from the set-up of the PET/SPECT laboratory to the routine experimental activity

Molecular imaging can be defined as the visual representation, characterization and quantification of biological processes at the cellular and subcellular levels within intact living organisms. Generally speaking, molecular imaging involves specialized instrumentation, used alone or in combination with targeted imaging agents, to visualize tissue characteristics and/or biochemical markers. The field of molecular imaging is highly multidisciplinary, drawing from many areas of science, including, but not limited to, molecular biology, biochemistry, physiology, physics, engineering, genetics, mathematics, chemistry, pharmacology, immunology, and medicine. Molecular imaging of living subjects can trace its roots back to nuclear medicine, nevertheless many techniques are now possible. In fact, techniques using optical signaling, as well as signaling using magnetic resonance imaging (MRI), ultrasound (US), Raman, photoacoustics (PA), and computed tomography (CT), have also been steadily increasing. And although still in its infancy, molecular imaging is showing enormous promise in the areas of diagnostics, therapy monitoring, drug discovery and development, and understanding nanoscale reactions such as protein-protein interactions and enzymatic conversion. Biomedical research utilizing small animals such as mice and rats has expanded dramatically in the past few years as molecular biology and imaging techniques open new opportunities to investigate models of disease. The growing number of mouse and rat experiments, coupled with the increasing number of dedicated small animal imaging systems such as microPET, optical, microCT, microMRI, ultrasound and microSPECT, has led to the development of common technical centers for imaging small animals. Increasingly sophisticated molecular probes and tool sets allow researchers to examine multiple processes at once in the same animal by using different light wavelengths (optical), various molecular imaging probes (PET and SPECT) and different contrast agents (MRI and CT), as well as to define the anatomical structures in which these processes take place. This, in turn, has led to a demand for comprehensive, multimodality imaging facilities that can house animals, support imaging systems, and provide investigators with the tools, methods, and other infrastructure necessary for successful imaging experiments. The realization of the Center of Excellence in Preclinical Imaging (CEIP) is part of this expansions. The CEIP is an Academic/Industry partnership and offers to universities, research centers and companies know-how and methodologies based on imaging techniques in order to facilitate and speed up the process of development of new diagnostic and therapeutic solutions. This thesis mainly describes two topics of the experience within the CEIP: the set-up of the PET/SPECT laboratory and a few small animal imaging studies. Concerning the set-up of the PET/SPECT laboratory, we focused on radioprotection issues such as: - features of the employed sources. - Selection of the rooms reserved for radioactive employing and description of the equipment positioning. - Shielding calculation. - Evaluation of the radiation exposure to both personnel and public. - Management of the radioactive wastes and residuals. - Classification of the areas and of the workers. About animal experiments, a few case studies have been reported. - A PET study performed with [18]F and [68]Ga to assess the response to Dasatinib treatment in PC-3 prostate tumor-bearing nude mice. - A longitudinal SPECT concerning the evaluation of the $^{99m}$Tc-rhAnnexin V-128 imaging effectiveness for diagnosis and monitoring anti-rheumatic therapies in a collagen induced arthritis (CIA) model in mice. - A multimodality study realized by combining the 7 T MRI scanner with the YAP-(S)PET scanner. The PET/MRI acquisitions were performed in sequential mode with a hand-made bed support that allowed to keep the animal in a fixed position

Advances in navigation and intraoperative imaging for intraoperative electron radiotherapy

Mención Internacional en el título de doctorEsta tesis se enmarca dentro del campo de la radioterapia y trata específicamente sobre la radioterapia intraoperatoria (RIO) con electrones. Esta técnica combina la resección quirúrgica de un tumor y la radiación terapéutica directamente aplicada sobre el lecho tumoral post-resección o sobre el tumor no resecado. El haz de electrones de alta energía es colimado y conducido por un aplicador específico acoplado a un acelerador lineal. La planificación de la RIO con electrones es compleja debido a las modificaciones geométricas y anatómicas producidas por la retracción de estructuras y la eliminación de tejidos cancerosos durante la cirugía. Actualmente, no se dispone del escenario real en este tipo de tratamientos (por ejemplo, la posición/orientación del aplicador respecto a la anatomía del paciente o las irregularidades en la superficie irradiada), sólo de una estimación grosso modo del tratamiento real administrado al paciente. Las imágenes intraoperatorias del escenario real durante el tratamiento (concretamente imágenes de tomografía axial computarizada [TAC]) serían útiles no sólo para la planificación intraoperatoria, sino también para registrar y evaluar el tratamiento administrado al paciente. Esta información es esencial en estudios prospectivos. En esta tesis se evaluó en primer lugar la viabilidad de un sistema de seguimiento óptico de varias cámaras para obtener la posición/orientación del aplicador en los escenarios de RIO con electrones. Los resultados mostraron un error de posición del aplicador inferior a 2 mm (error medio del centro del bisel) y un error de orientación menor de 2º (error medio del eje del bisel y del eje longitudinal del aplicador). Estos valores están dentro del rango propuesto por el Grupo de Trabajo 147 (encargo del Comité de Terapia y del Subcomité para la Mejora de la Garantía de Calidad y Resultados de la Asociación Americana de Físicos en Medicina [AAPM] para estudiar en radioterapia externa la exactitud de la localización con métodos no radiográficos, como los sistemas infrarrojos). Una limitación importante de la solución propuesta es que el aplicador se superpone a la imagen preoperatoria del paciente. Una imagen intraoperatoria proporcionaría información anatómica actualizada y permitiría estimar la distribución tridimensional de la dosis. El segundo estudio específico de esta tesis evaluó la viabilidad de adquirir con un TAC simulador imágenes TAC intraoperatorias de escenarios reales de RIO con electrones. No hubo complicaciones en la fase de transporte del paciente utilizando la camilla y su acople para el transporte, o con la adquisición de imágenes TAC intraoperatorias en la sala del TAC simulador. Los estudios intraoperatorios adquiridos se utilizaron para evaluar la mejora obtenida en la estimación de la distribución de dosis en comparación con la obtenida a partir de imágenes TAC preoperatorias, identificando el factor dominante en esas estimaciones (la región de aire y las irregularidades en la superficie, no las heterogeneidades de los tejidos). Por último, el tercer estudio específico se centró en la evaluación de varias tecnologías TAC de kilovoltaje, aparte del TAC simulador, para adquirir imágenes intraoperatorias con las que estimar la distribución de la dosis en RIO con electrones. Estos dispositivos serían necesarios en el caso de disponer de aceleradores lineales portátiles en el quirófano ya que no se aprobaría mover al paciente a la sala del TAC simulador. Los resultados con un maniquí abdominal mostraron que un TAC portátil (BodyTom) e incluso un acelerador lineal con un TAC de haz de cónico (TrueBeam) serían adecuados para este propósito.This thesis is framed within the field of radiotherapy, specifically intraoperative electron radiotherapy (IOERT). This technique combines surgical resection of a tumour and therapeutic radiation directly applied to a post-resection tumour bed or to an unresected tumour. The high-energy electron beam is collimated and conducted by a specific applicator docked to a linear accelerator (LINAC). Dosimetry planning for IOERT is challenging owing to the geometrical and anatomical modifications produced by the retraction of structures and removal of cancerous tissues during the surgery. No data of the actual IOERT 3D scenario is available (for example, the applicator pose in relation to the patient’s anatomy or the irregularities in the irradiated surface) and consequently only a rough approximation of the actual IOERT treatment administered to the patient can be estimated. Intraoperative computed tomography (CT) images of the actual scenario during the treatment would be useful not only for intraoperative planning but also for registering and evaluating the treatment administered to the patient. This information is essential for prospective trials. In this thesis, the feasibility of using a multi-camera optical tracking system to obtain the applicator pose in IOERT scenarios was firstly assessed. Results showed that the accuracy of the applicator pose was below 2 mm in position (mean error of the bevel centre) and 2º in orientation (mean error of the bevel axis and the longitudinal axis), which are within the acceptable range proposed in the recommendation of Task Group 147 (commissioned by the Therapy Committee and the Quality Assurance and Outcomes Improvement Subcommittee of the American Association of Physicists in Medicine [AAPM] to study the localization accuracy with non-radiographic methods such as infrared systems in external beam radiation therapy). An important limitation of this solution is that the actual pose of applicator is superimposed on a patient’s preoperative image. An intraoperative image would provide updated anatomical information and would allow estimating the 3D dose distribution. The second specific study of this thesis evaluated the feasibility of acquiring intraoperative CT images with a CT simulator in real IOERT scenarios. There were no complications in the whole procedure related to the transport step using the subtable and its stretcher or the acquisition of intraoperative CT images in the CT simulator room. The acquired intraoperative studies were used to evaluate the improvement achieved in the dose distribution estimation when compared to that obtained from preoperative CT images, identifying the dominant factor in those estimations (air gap and the surface irregularities, not tissue heterogeneities). Finally, the last specific study focused on assessing several kilovoltage (kV) CT technologies other than CT simulators to acquire intraoperative images for estimating IOERT dose distribution. That would be necessary when a mobile electron LINAC was available in the operating room as transferring the patient to the CT simulator room could not be approved. Our results with an abdominal phantom revealed that a portable CT (BodyTom) and even a LINAC with on-board kV cone-beam CT (TrueBeam) would be suitable for this purpose.Programa Oficial de Doctorado en Multimedia y ComunicacionesPresidente: Joaquín López Herráiz.- Secretario: María Arrate Muñoz Barrutia.- Vocal: Óscar Acosta Tamay

Particle Physics Reference Library

This second open access volume of the handbook series deals with detectors, large experimental facilities and data handling, both for accelerator and non-accelerator based experiments. It also covers applications in medicine and life sciences. A joint CERN-Springer initiative, the “Particle Physics Reference Library” provides revised and updated contributions based on previously published material in the well-known Landolt-Boernstein series on particle physics, accelerators and detectors (volumes 21A,B1,B2,C), which took stock of the field approximately one decade ago. Central to this new initiative is publication under full open access