Cyclotron Production and Biomedical Imaging Applications of the PET Isotope Manganese-52

Manganese is an important element for biomedical research because of its roles as an essential micronutrient and as a neurotoxin from chronic elevated exposure, as well as the role of manganese(II) as a paramagnetic core for contrast agents in T1-weighted magnetic resonance imaging (MRI). Using a radiotracer of manganese provides excellent sensitivity for studying these phenomena, but only 52Mn met the criteria for our experiments: (1) a half-life (t1/2=5.6 days) that was long enough to examine timepoints over several days, (2) a half-life that was short enough to emit sufficient counts for a realistic scan time, and (3) emitted radiation of a variety and energy that were appropriate for existing pre-clinical imaging modalities. Manganese-52 is well-suited for imaging with positron emission tomography (PET) because it emits positrons with a low energy (E+=242 keV), which improves spatial resolution, and with an acceptable total abundance for positron emission (I+=29.6%) for adequate signal. Manganese-52 was produced on site by the 52Cr(p,n)52Mn reaction by bombarding non-enriched chromium (52Cr: 83.8%) with ~13 MeV protons that were accelerated in the CS-15 cyclotron at Washington University School of Medicine in St. Louis. Bombardments of stacks of thin chromium metal foils were used to measure nuclear cross-sections for the natCr(p,x)52,52m,54Mn reactions, with results that agreed closely to simulations and published results. Manganese-52 was separated chemically from bombarded chromium metal by cation- or anion-exchange chromatography. The separated product was used in experiments that included biodistribution by injection or inhalation, PET/CT or PET/MR in phantoms and rodents, and radiolabelling of a Mn(II)-based contrast agent for T1-weighted MRI. To reduce radiation dose to production personnel, we designed a remotely controlled, semi-automated module for the remote separation of 52Mn inside a lead hot cell. This module was similar to other modules that we designed, built, and tested for the routine, scaled-up production of larger quantities of the PET isotopes 89Zr and 86Y. We anticipate that the module for 52Mn will be completed, routine production of greater quantities of 52Mn will be achieved, and this radioisotope will continue to be used to study and image the interesting aspects and behaviors of manganese chemistry

Implementation of a clinical dosimetry workflow to perform personalized dosimetry for internal radiotherapy

La médecine nucléaire est une spécialité médicale qui étudie la physiologie des organes et le métabolisme de divers types de tumeurs. La médecine nucléaire utilise des produits pharmaceutiques liés à un isotope radioactif. La radiothérapie interne vectorisée (RIV) est une spécialité de la médecine nucléaire où le vecteur est dirigé vers des cibles, généralement des tumeurs, et où l'action des rayonnements ionisants vise à détruire les tumeurs. Le suivi et l'optimisation de la RMT nécessitent l'évaluation de l'irradiation délivrée au patient (dosimétrie). Il y a un manque de standardisation en dosimétrie interne. Cette thèse propose une approche standardisée avec des flux de travail descriptifs pour la dosimétrie clinique. Un logiciel appelé OpenDose3D, basé sur 3D-Slicer en tant que module open source mettant en oeuvre les flux de travail proposés, est développé, validé et mis à la disposition du public. Le module a été utilisé en recherche clinique dans le projet MEDIRAD.Nuclear medicine is a medical specialty that studies the physiology of organs and the metabo-lism of various types of tumors. Nuclear medicine uses pharmaceuticals bound to a radioactive isotope. Molecular radiotherapy (MRT) is a specialty of nuclear medicine where the vector is directed to targets, usually tumors, and the action of ionizing radiation is aimed at destroying tumors. The follow-up and optimization of MRT requires the evaluation of the irradiation delivered to the patient (dosimetry). There is a lack of standardization in internal dosimetry. This thesis provides a standardized approach with descriptive clinical dosimetry workflows. A software named OpenDose3D, based in 3D-Slicer and implementing the proposed workflows was developed, validated and was made publicly available as an open source module. The module was used in clinical research within the MEDIRAD project

Otimização do modo de registo de dados durante a técnica de Perfusão Isolada dos Membros

Cancer is a disease in which the cells of our organism, due to mutations in their DNA, divide without control and acquire malignant properties and, during this process of uncontrolled division, invade other tissues and don’t die. Cancer cells have the ability to spread through the body using the circulatory and lymphatic systems, giving rise to metastases. With regard to cutaneous neoplasms, the therapy chosen for surgically dispersed and unresectable metastases involved amputation of the sick limb, however, many complications and short time intervals between treatment and the appearance of new lesions were associated. In 1957, an innovative technique emerges and proves to be extremely effective and avoids limb amputation: Isolated Limb Perfusion performed with Melphalan and TNF-α. The main objective of this procedure is to isolate the limb affected by the disease from the systemic circulation so that it is possible to administer very high doses of chemotherapy without any collateral damage. In this sense, it is necessary to have a control of blood leaks from the limb to the systemic circulation, in order to ensure that no other organ or tissue is compromised. The Portuguese Institute of Oncology (IPO) of Porto is one of the worldwide institutions that practice this type of surgical interventions, reporting an annual increase in the number of occurrences year after year. Consequently, this progressive increase and coupled with the fact that this leak control is impractical and time-consuming, led this institution to join Instituto Superior de Engenharia do Porto (ISEP) to develop an application that, in combination with an extracorporeal counter equipment called Neoprobe Gamma Detector System is able to record the values obtained automatically and allow monitoring possible leaks

Goggle Augmented Imaging and Navigation System for Fluorescence-Guided Surgery

Surgery remains the only curative option for most solid tumors. The standard-of-care usually involves tumor resection and sentinel lymph node biopsy for cancer staging. Surgeons rely on their vision and touch to distinguish healthy from cancer tissue during surgery, often leading to incomplete tumor resection that necessitates repeat surgery. Sentinel lymph node biopsy by conventional radioactive tracking exposes patients and caregivers to ionizing radiation, while blue dye tracking stains the tissue highlighting only superficial lymph nodes. Improper identification of sentinel lymph nodes may misdiagnose the stage of the cancer. Therefore there is a clinical need for accurate intraoperative tumor and sentinel lymph node visualization. Conventional imaging modalities such as x-ray computed tomography, positron emission tomography, magnetic resonance imaging, and ultrasound are excellent for preoperative cancer diagnosis and surgical planning. However, they are not suitable for intraoperative use, due to bulky complicated hardware, high cost, non-real-time imaging, severe restrictions to the surgical workflow and lack of sufficient resolution for tumor boundary assessment. This has propelled interest in fluorescence-guided surgery, due to availability of simple hardware that can achieve real-time, high resolution and sensitive imaging. Near-infrared fluorescence imaging is of particular interest due to low background absorbance by photoactive biomolecules, enabling thick tissue assessment. As a result several near-infrared fluorescence-guided surgery systems have been developed. However, they are limited by bulky hardware, disruptive information display and non-matched field of view to the user. To address these limitations we have developed a compact, light-weight and wearable goggle augmented imaging and navigation system (GAINS). It detects the near-infrared fluorescence from a tumor accumulated contrast agent, along with the normal color view and displays accurately aligned, color-fluorescence images via a head-mounted display worn by the surgeon, in real-time. GAINS is a platform technology and capable of very sensitive fluorescence detection. Image display options include both video see-through and optical see-through head-mounted displays for high-contrast image guidance as well as direct visual access to the surgical bed. Image capture options from large field of view camera as well high magnification handheld microscope, ensures macroscopic as well as microscopic assessment of the tumor bed. Aided by tumor targeted near-infrared contrast agents, GAINS guided complete tumor resection in subcutaneous, metastatic and spontaneous mouse models of cancer with high sensitivity and specificity, in real-time. Using a clinically-approved near-infrared contrast agent, GAINS provided real-time image guidance for accurate visualization of lymph nodes in a porcine model and sentinel lymph nodes in human breast cancer and melanoma patients with high sensitivity. This work has addressed issues that have limited clinical adoption of fluorescence-guided surgery and paved the way for research into developing this approach towards standard-of-care practice that can potentially improve surgical outcomes in cancer

[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)

A software system for radionuclide dosimetry with applications.

Radiation dosimetry is necessary for optimising radiation-based medical procedures for individual patients but in the field of nuclear medicine there are few widely available or widely used tools for performing this kind of analysis. Those tools that are available tend to focus on one particular component of the dosimetry problem and integrating tools to form a complete system is left to the end-user. A software system for performing individual, image-based dosimetry analysis of nuclear medicine studies has been developed and validated. The system consists of a suite of tools that use common file formats and data models. The tools can be integrated to form applications by means of a simple scripting system. One tool is a gamma camera simulator that can produce realistic images of dynamic activity distributions in planar or tomographic formats. Simulated imaging studies produced by this tool are used to validate the other tools in the system. In addition, the system implements a method of simulation assisted quantitation which is shown to achieve high accuracy in both software and physical phantom studies. The system is applied to the dosimetry of I-131 Lipiodol, a therapeutic agent used to treat primary and secondary cancers of the liver. Simulation studies are used to validate the analytic methods used. Studies of a series of patients, treated over a period 10 years, are retrospectively analysed using a selection of methods appropriate to the available data. The results of the analysis demonstrated a large range of lung doses from 1 to 10 Gy/GBq administered. The median absorbed dose in liver was 3 Gy (range 1 - 10 Gy) and the median absorbed dose in tumor was 19 Gy (range 5 - 84 Gy). The large individual variation reinforces the necessity of individualised dosimetry for treatment planning and follow up

Design and Evaluation of a Novel Lens-Based SPECT System Based on Laue Lens Gamma Diffraction: GEANT4/GAMOS Monte Carlo Study

Abstract While improvements in SPECT imaging techniques constitute a significant advance in biomedical science and cancer diagnosis, their limited spatial resolution has hindered their application to small animal research and early tumour detection. Using recent breakthroughs established by the high-energy astrophysics community, focusing X-ray optics provides a method to overcome the paradigm of low resolution and presents the possibility of imaging small objects with sub-millimetre resolution. This thesis aims to tackle the constraints associated with the current SPECT imaging designs by exploiting the notion of focusing high energy photons through Laue lens diffraction and developing a means of performing gamma rays imaging that would not rely on parallel or pinhole collimators. The gradual development of the novel system is discussed, starting from the single, modular, and multi-Laue lens-based SPECT. A customized 3D reconstruction algorithm was developed to reconstruct an accurate 3D radioactivity distribution from focused projections. A plug-in implementing the Laue diffraction concept was developed and used to model gamma rays focusing in the GEANT4 toolkit. The plug-in will be incorporated into GEANT4 upon final approval from its developers. The single lens-based, modular lens-based and multi lens-based SPECT models detected one hit per 42 source photons (sensitivity of 790 ⁄), three hits per 42 source photons (sensitivity of 2,373 ⁄), and one hit per 20 source photons (sensitivity of 1,670 ⁄), respectively. Based on the generated 3D reconstructed images, the achievable spatial resolution was found to be 0.1 full width at half maximum (FWHM). The proposed design’s performance parameters were compared against the existing SIEMENS parallel LEHR and multi-pinhole (5-MWB-1.0) Inveon SPECT. The achievable spatial resolution is decoupled from the sensitivity of the system, which is in stark contrast with the existing collimators that suffer from the resolution-sensitivity trade-off and are limited to a resolution of 2 . The proposed system allows discrimination between adjacent volumes as small as 0.113 , which is substantially smaller than what can be imaged by any existing SPECT or PET system. The proposed design could lay the foundation for a new SPECT imaging technology akin to a combination of tomosynthesis and lightfield imaging