Benchtop systems for in vivo molecular screening of labeled compounds, as a tool to speed up drug research.

BACKGROUND: For every new drug, >10,000 candidate molecules are tested for ~15 years. This is the daily mission of thousands research teams worldwide. It is well proven that small animal imaging speeds up this work, increases accuracy and decreases costs. However, commercial imaging systems have high purchase cost, require high service contracts, special facilities and trained staff. Thus, they are affordable to only few large research centres and not to the majority of small and medium research teams internationally. There are two main reasons that urge the addressing of this problem at large scale now: Firstly, small animal imaging started in 2000 and quickly research community and pharma industry understood its value, which opened preclinical imaging market (>2.5 Bil $). Continuous evolution in medicine and biology clearly shows the need to speed up research using new tools. Asian countries rapidly invest funds in drug research, enlarging existing market. Secondly, until recently such systems were based on complicated electronics and expensive components. Evolution in detector technology, electronics, software and 3D printing, made feasible the development of benchtop imaging systems, with attractive end user price. MATERIALS AND METHODS: Being an active partner of numerous international and national projects, we tried to identify the main requirements that an imaging system should have, in order to become a screening tool for daily use. Thus, we recently developed a new generation of affordable, but high-performance imaging systems, which can fulfil the daily needs of all research labs activated in preclinical research. Our technology covers the field of SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) imaging, while an optical and x-ray imaging system is under development. The systems are based on well tested technology, including pixeliated scintillators, Position Sensitive Photomultipliers, programmable ADCs (Analog to Digital Converters) and FPGAs (Field Programmable Gate Arrays) and are connected with a standard laptop through USB and Ethernet connection. The systems are named "eyes-series" and have been already tested for fast screening of small animals injected with labeled compounds including peptides, antibodies and nanoparticles. Besides their performance, they are offered at a fraction of the cost of the commercial ones, comparable to standard lab equipment such as HPLC, gamma counter etc, opening new prospects in preclinical research. The first system is called "γ-eye™" and it is a dedicated system for imaging photons (γ-rays) which are emitted from radiolabelled biomolecules (2D-SPECT). The second system is called "ß-eye™" and detects positrons (ß-rays) from similar biomolecules (2D-PET). They both have dimensions which are 35x35x30cm and weight which is less that 30kgr. The spatial resolution of both systems is <2mm and their energy resolution <20%. Their sensitivity allows real time imaging for the first second post injection, while images are shown in real time during acquisition. They allow recording of fast frames, down to 1min, thus it is possible to perform fast kinetic studies. Finally, they are both provided along with a laptop that has preinstalled the required software, named "VISUAL-eyes". RESULTS: The technical specifications and performance evaluation of our technology will be presented. Different applications including oncology, regenerative medicine, nanomedicine and lung imaging will be given. Finally, the results of the comparison against high performance systems and a typical workflow for optimizing throughput will be demonstrated.

Comparison of the magnetic, radiolabeling, hyperthermic and biodistribution properties of hybrid nanoparticles bearing CoFe2O4 and Fe3O4 metal cores.

Metal oxide nanoparticles, hybridized with various polymeric chemicals, represent a novel and breakthrough application in drug delivery, hyperthermia treatment and imaging techniques. Radiolabeling of these nanoformulations can result in new and attractive dual-imaging agents as well as provide accurate in vivo information on their biodistribution profile. In this paper a comparison study has been made between two of the most promising hybrid core-shell nanosystems, bearing either magnetite (Fe3O4) or cobalt ferrite (CoFe2O4) cores, regarding their magnetic, radiolabeling, hyperthermic and biodistribution properties. While hyperthermic properties were found to be affected by the metal-core type, the radiolabeling ability and the in vivo fate of the nanoformulations seem to depend critically on the size and the shell composition.

ß-eye: A benchtop system for in vivo molecular screening of labeled compounds.

Preclinical nuclear molecular imaging speeds up the mean time from synthesis to market, in drug development process. Commercial imaging systems have in general high cost, require high-cost service contracts, special facilities and trained staff. In the current work, we present ß-eye, a benchtop system for in vivo molecular screening of labeled compounds with Positron Emission Tomography (PET) isotopes. The developed system is based on a dual-head geometry, offering simplicity and decreased cost. The goal of the design is to provide 2D, real-time radionuclide images of mice, allowing the recording of fast frames and thus perform fast kinetic studies, with spatial resolution of ∼2 mm. Performance evaluation demonstrates the ability of ß-eye to provide quantitative results for injected activities lower than 1.5 MBq, which is adequate for pharmacodynamic studies in small mice.

PET Counting Response Variability Depending on Tumor Location, Activity, and Patient Obesity: A Feasibility Study of Solitary Pulmonary Nodule Using Monte Carlo.

We aim to investigate the counting response variations of positron emission tomography (PET) scanners with different detector configurations in the presence of solitary pulmonary nodule (SPN). Using experimentally validated Monte Carlo simulations, the counting performance of four different scanner models with varying tumor activity, location, and patient obesity is represented using a noise equivalent count rate (NECR). NECR is a well-established quantitative metric which has positive correlation with clinically perceived image quality. The combined effect of tumor displacement and increased activity shows a linear ascending trend for NECR with slope ranges of (12.5-18.2)*10-3 (kBq/cm3)-1 for three-ring (3R) scanners and (15.3-21.5)*10-3 (kBq/cm3)-1 for four-ring (4R). The trend for the combined effect of tumor displacement and patient obesity is exponential decay with 3R configurations weakly dependent on the patient obesity if the tumor is located at the center of the field of view with exponent's range of (6.6-33.8)*10-2cm-1. The dependence is stronger for 4R scanners (9.6-38.5)*10-2cm-1. The analysis indicates that quantitative PET data from the same SPN patient possibly examined in different time points (e.g., during staging or for the evaluation of treatment response) are affected by the different detector configurations and need to be normalized with patient weight, activity, and tumor location to reduce unwanted bias of the diagnosis. This paper provides also with a proof of concept for the ability of properly tuned simulations to provide additional insights into the counting response variability especially in tumor types where often borderline decisions have to be made regarding their characterization.

Nanomedicinal Approach of Getting Across the Brood-Brain Barrier with Nanomedicinal Nanoparticles.

Passage into the brain has always been a major challenge for medicine in order to treat malfunctions of the central nervous system (CNS). The blood-brain-barrier (BBB) is a physical obstacle that controls the entrance of substances -including pharmaceuticals- into the brain. The application of nanotechnology in medicine, namely nanomedicine, is rapidly evolving and opens new prospects for brain imaging and drug delivery into the brain. Nanomedicine when combined with nuclear medicine can offer new, promising and innovative means towards this direction through radiolabeled nanoparticles. Nanoparticles radiolabeled with ß(-), γ- or ß(+)-emitters can cross the BBB and play major role in CNS imaging and/or drug delivery.

Evaluation of a SiPM array coupled to a Gd3Al2Ga3O12:Ce (GAGG:Ce) discrete scintillator.

PURPOSE: In this study, we present the results of the evaluation of the SensL ArraySL-4 photo-detector, coupled to a 6 × 6 GAGG:Ce scintillator array, with 2 × 2 × 5 mm(3) crystal size elements for possible applications in medical imaging detectors with focus in PET applications. Experimental evaluation was carried out with (22)Na and (137)Cs radioactive sources and the parameters studied were energy resolution and peak to valley ratio. METHODS: ArraySL-4 is a commercially available, 4 × 4 array detector covering an active area of 13.4 mm(2). The GAGG:Ce scintillator array used in this study has 0.1 mm thickness BaSO4 reflector material between the crystal elements. A symmetric resistive voltage division matrix was applied, which reduces the 16 outputs of the array to 4 position signals. A Field Programmable Gate Array was used for triggering and digital processing of the signal pulses acquired using free running Analog to Digital Converters. RESULTS: Raw images and horizontal profiles of the 6 × 6 GAGG:Ce scintillator array produced under 511 keV and 662 keV excitation are illustrated. Moreover, the energy spectra obtained with (22)Na and (137)Cs radioactive sources from a single 2 × 2 × 5 mm(3) GAGG:Ce scintillator are shown. The peak to valley ratio and the mean energy resolution values are reported. CONCLUSIONS: The acquired raw image of the GAGG:Ce crystal array under 511 keV excitation shows a clear visualization of all discrete scintillator elements with a mean peak to valley ratio equal to 40. The mean energy resolution was measured equal to 10.5% and 9% respectively under 511 keV and 662 keV irradiation.

Validation of the GATE Monte Carlo simulation platform for modelling a CsI(Tl) scintillation camera dedicated to small-animal imaging.

Monte Carlo simulations are increasingly used in scintigraphic imaging to model imaging systems and to develop and assess tomographic reconstruction algorithms and correction methods for improved image quantitation. GATE (GEANT4 application for tomographic emission) is a new Monte Carlo simulation platform based on GEANT4 dedicated to nuclear imaging applications. This paper describes the GATE simulation of a prototype of scintillation camera dedicated to small-animal imaging and consisting of a CsI(Tl) crystal array coupled to a position-sensitive photomultiplier tube. The relevance of GATE to model the camera prototype was assessed by comparing simulated 99mTc point spread functions, energy spectra, sensitivities, scatter fractions and image of a capillary phantom with the corresponding experimental measurements. Results showed an excellent agreement between simulated and experimental data: experimental spatial resolutions were predicted with an error less than 100 microns. The difference between experimental and simulated system sensitivities for different source-to-collimator distances was within 2%. Simulated and experimental scatter fractions in a [98-182 keV] energy window differed by less than 2% for sources located in water. Simulated and experimental energy spectra agreed very well between 40 and 180 keV. These results demonstrate the ability and flexibility of GATE for simulating original detector designs. The main weakness of GATE concerns the long computation time it requires: this issue is currently under investigation by the GEANT4 and the GATE collaborations.

Improving spatial resolution in SPECT with the combination of PSPMT based detector and iterative reconstruction algorithms.

This paper investigates the possibility of developing a SPECT system that combines the high spatial resolution of position sensitive photomultiplier tubes (PSPMTs) with the excellent performance of iterative reconstruction algorithms. A small field of view (FOV) camera based on a PSPMT and a pixelized scintillation crystal made of CsI(Tl) have been used for the acquisition of the projections. With the use of maximum likelihood expectation maximization (ML-EM) and ordered subsets expectation maximization (OSEM) slices of the object are obtained while three-dimensional (3D) reconstruction of the object is carried out using a modified marching cubes (MMC) algorithm. The spatial resolution of tomographic images obtained with the system was 2-3mm. The spatial resolution of a conventional system that uses filtered backprojection (FBP) for slices reconstruction was more than 9 mm.

A 3D high-resolution gamma camera for radiopharmaceutical studies with small animals.

The results of studies conducted with a small field of view tomographic gamma camera based on a Position Sensitive Photomultiplier Tube are reported. The system has been used for the evaluation of radiopharmaceuticals in small animals. Phantom studies have shown a spatial resolution of 2mm in planar and 2-3mm in tomographic imaging. Imaging studies in mice have been carried out both in 2D and 3D. Conventional radiopharmaceuticals have been used and the results have been compared with images from a clinically used system.

SU-E-I-88: Realistic Pathological Simulations of the NCAT and Zubal Anthropomorphic Models, Based on Clinical PET/CT Data.

PURPOSE: In the present study a patient-specific dataset of realistic PET simulations was created, taking into account the variability of clinical oncology data. Tumor variability was tested in the simulated results. A comparison of the produced simulated data was performed to clinical PET/CT data, for the validation and the evaluation of the procedure. METHODS: Clinical PET/CT data of oncology patients were used as the basis of the simulated variability inserting patient-specific characteristics in the NCAT and the Zubal anthropomorphic phantoms. GATE Monte Carlo toolkit was used for simulating a commercial PET scanner. The standard computational anthropomorphic phantoms were adapted to the CT data (organ shapes), using a fitting algorithm. The activity map was derived from PET images. Patient tumors were segmented and inserted in the phantom, using different activity distributions. RESULTS: The produced simulated data were reconstructed using the STIR opensource software and compared to the original clinical ones. The accuracy of the procedure was tested in four different oncology cases. Each pathological situation was illustrated simulating a) a healthy body, b) insertion of the clinical tumor with homogenous activity, and c) insertion of the clinical tumor with variable activity (voxel-by-voxel) based on the clinical PET data. The accuracy of the presented dataset was compared to the original PET/CT data. Partial Volume Correction (PVC) was also applied in the simulated data. CONCLUSIONS: In this study patient-specific characteristics were used in computational anthropomorphic models for simulating realistic pathological patients. Voxel-by-voxel activity distribution with PVC within the tumor gives the most accurate results. Radiotherapy applications can utilize the benefits of the accurate realistic imaging simulations, using the anatomicaland biological information of each patient. Further work will incorporate the development of analytical anthropomorphic models with motion and cardiac correction, combined with pathological patients to achieve high accuracy in tumor imaging. This research was supported by the Joint Research and Technology Program between Greece and France; 2009-2011 (protocol ID: 09FR103).

3D calculation of absorbed dose for 131I-targeted radiotherapy: a Monte Carlo study.

Various methods, such as those developed by the Medical Internal Radiation Dosimetry (MIRD) Committee of the Society of Nuclear Medicine or employing dose point kernels, have been applied to the radiation dosimetry of (131)I radionuclide therapy. However, studies have not shown a strong relationship between tumour absorbed dose and its overall therapeutic response, probably due in part to inaccuracies in activity and dose estimation. In the current study, the GATE Monte Carlo computer code was used to facilitate voxel-level radiation dosimetry for organ activities measured in an (131)I-treated thyroid cancer patient. This approach allows incorporation of the size, shape and composition of organs (in the current study, in the Zubal anthropomorphic phantom) and intra-organ and intra-tumour inhomogeneities in the activity distributions. The total activities of the tumours and their heterogeneous distributions were measured from the SPECT images to calculate the dose maps. For investigating the effect of activity distribution on dose distribution, a hypothetical homogeneous distribution of the same total activity was considered in the tumours. It was observed that the tumour mean absorbed dose rates per unit cumulated activity were 0.65E-5 and 0.61E-5 mGY MBq(-1) s(-1) for the uniform and non-uniform distributions in the tumour, respectively, which do not differ considerably. However, the dose-volume histograms (DVH) show that the tumour non-uniform activity distribution decreases the absorbed dose to portions of the tumour volume. In such a case, it can be misleading to quote the mean or maximum absorbed dose, because overall response is likely limited by the tumour volume that receives low (i.e. non-cytocidal) doses. Three-dimensional radiation dosimetry, and calculation of tumour DVHs, may lead to the derivation of clinically reliable dose-response relationships and therefore may ultimately improve treatment planning as well as response assessment for radionuclide therapy.