Radiation Dosimetry Studies Research Articles

Development, characterization and radiation dosimetry evaluation of Bovine gelatin crosslinked with Gum Arabic Aldehyde as brain phantom gel material in radiation therapy

Brain phantom gel materials are of critical importance for accuracy of dosimetry, treatment planning and quality assurance in radiotherapy. Development of reliable and realistic phantoms enhances improved radiotherapy practices. Gel dosimeters have unique property to record radiation dose distribution in three dimensions. Polymer gels also have added advantages for brachytherapy dosimetry. Objective of the study was to develop an alternative polymeric gel material equivalent to human brain for conducting radiation dosimetry studies in radiotherapy. Hydrogel prepared from gelatin and gum arabic aldehyde was used to develop a brain phantom gel material for radiation dosimetry in radiotherapy. The results of comparative studies with G-GAAB gel strongly suggest, the gel can successfully be utilized as a brain equivalent material for radiation dosimetry in place of standard water phantom by measuring (a) CT number values (b) mass attenuation coefficient values at two X-ray energies used in radiation treatment (c) absorbed dose values at different depths for various setup conditions. The midrange CT number values inside gel material and that of human brain measured from CT images were 25.5HU and 25HU respectively with a variation of 2%. The mass attenuation coefficients for brain, water and gel material at 6MV photons were 0.0275cm2/g, 0.0280cm2/g,0.0270cm2/g and for 15MV photons, the attenuation coefficients were 0.0192cm2/g, 0.0190cm2/g and 0.0180cm2/g respectively. The percentage deviation of all measurements of absorbed dose values in gel phantom material, compared with the values of standard water phantom at various radiation dosimetry setup parameters, is less than 2%.

Recent review of natural and artificial background radiation dosimetry studies in Saudi Arabia.

This paper includes a review of the natural background radiation of the Kingdom of Saudi Arabia. The review deals with natural radioactivity measurements conducted in the past few decades in the Kingdom. The numerous research works reviewed refer to different materials soils processed building material, terrestrial (dwellings) and mining sites. For the measurements, different experimental techniques were adopted. The highest mean specific activity of 238U, 232Th and 40K in soil samples was found to be 39.0, 25.6, and 343.0Bq/kg, respectively. While the world average values are 33, 45 and 420Bq/kg, respectively. For building materials, the highest mean values for 226Ra, 232Th and 40K were 89, 106 and 773Bq/kg, respectively. The mean indoor and outdoor dose rates were 455µGy/y (Riyadh City) and 883µGy/y (Al-Khamis City), respectively. For the mining sites the mean values for 238U, 226Ra, 228Ra, gross α and gross β, were 0.12, 0.33, 21, 0.78 and 2.44Bq/kg, respectively. Based on the available data it is concluded that most of the natural background radiation levels in the measured locations were within acceptable limits, while a few isolated locations showed elevated dose rates. This review suggests that new improved radiological survey methods be employed to cover the entire country, and that areas identified with comparably high dose rates be re-assessed, especially, in dwellings and mining sites.

Patient-specific fetal radiation dosimetry for pregnant patients undergoing abdominal and pelvic CT imaging.

Accurate estimation of fetal radiation dose is crucial for risk-benefit analysis of radiological imaging, while the radiation dosimetry studies based on individual pregnant patient are highly desired. To use Monte Carlo calculations for estimation of fetal radiation dose from abdominal and pelvic computed tomography (CT) examinations for a population of patients with a range of variations in patients' anatomy, abdominal circumference, gestational age (GA), fetal depth (FD), and fetal development. Forty-four patient-specific pregnant female models were constructed based on CT imaging data of pregnant patients, with gestational ages ranging from 8 to 35weeks. The simulation of abdominal and pelvic helical CT examinations was performed on three validated commercial scanner systems to calculate organ-level fetal radiation dose. The absorbed radiation dose to the fetus ranged between 0.97 and 2.24 mGy, with an average of 1.63±0.33 mGy. The CTDIvol -normalized fetal dose ranged between 0.56 and 1.30, with an average of 0.94±0.25. The normalized fetal organ dose showed significant correlations with gestational age, maternal abdominal circumference (MAC), and fetal depth. The use of ATCM technique increased the fetal radiation dose in some patients. A technique enabling the calculation of organ-level radiation dose to the fetus was developed from models of actual anatomy representing a range of gestational age, maternal size, and fetal position. The developed maternal and fetal models provide a basis for reliable and accurate radiation dose estimation to fetal organs.

A high-resolution pediatric female whole-body numerical model with comparison to a male model

Objective. Numerical models are central in designing and testing novel medical devices and in studying how different anatomical changes may affect physiology. Despite the numerous adult models available, there are only a few whole-body pediatric numerical models with significant limitations. In addition, there is a limited representation of both male and female biological sexes in the available pediatric models despite the fact that sex significantly affects body development, especially in a highly dynamic population. As a result, we developed Athena, a realistic female whole-body pediatric numerical model with high-resolution and anatomical detail. Approach. We segmented different body tissues through Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) images of a healthy 3.5 year-old female child using 3D Slicer. We validated the high anatomical accuracy segmentation through two experienced sub-specialty-certified neuro-radiologists and the inter and intra-operator variability of the segmentation results comparing sex differences in organ metrics with physiologic values. Finally, we compared Athena with Martin, a similar male model, showing differences in anatomy, organ metrics, and MRI dosimetric exposure. Main results. We segmented 267 tissue compartments, which included 50 brain tissue labels. The tissue metrics of Athena displayed no deviation from the literature value of healthy children. We show the variability of brain metrics in the male and female models. Finally, we offer an example of computing Specific Absorption Rate and Joule heating in a toddler/preschooler at 7 T MRI. Significance. This study introduces a female realistic high-resolution numerical model using MRI and CT scans of a 3.5 year-old female child, the use of which includes but is not limited to radiofrequency safety studies for medical devices (e.g. an implantable medical device safety in MRI), neurostimulation studies, and radiation dosimetry studies. This model will be open source and available on the Athinoula A. Martinos Center for Biomedical Imaging website.

Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [11C]CHDI-00485180-R and [11C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin.

Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [11C]CHDI-00485180-R ([11C]CHDI-180R) and [11C]CHDI-00485626 ([11C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models. Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5years; 2 F) for [11C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8years; 2 F) for [11C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1. There were no clinically relevant adverse events. The mean effective dose (ED) for [11C]CHDI-180R was 4.58 ± 0.65 μSv/MBq, with highest absorbed doses for liver (16.9μGy/MBq), heart wall (15.9μGy/MBq) and small intestine (15.8μGy/MBq). Mean ED for [11C]CHDI-626 was 5.09 ± 0.06 μSv/MBq with the highest absorbed doses for the gallbladder (26.5μGy/MBq), small intestine (20.4μGy/MBq) and liver (19.6μGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [11C]CHDI-180R, but for [11C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. [11C]CHDI-180R and [11C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11C-ligands. While [11C]CHDI-180R has promising kinetic properties in the brain, [11C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma. EudraCT number 2020-002129-27. gov NCT05224115 (retrospectively registered).

Construction of a digital fetus library for radiation dosimetry.

Accurate estimations of fetal absorbed dose and radiation risks are crucial for radiation protection and important for radiological imaging research owing to the high radiosensitivity of the fetus. Computational anthropomorphic models have been widely used in patient-specific radiation dosimetry calculations. In this work, we aim to build the first digital fetal library for more reliable and accurate radiation dosimetry studies. Computed tomography (CT) images of abdominal and pelvic regions of 46 pregnant females were segmented by experienced medical physicists. The segmented tissues/organs include the body contour, skeleton, uterus, liver, kidney, intestine, stomach, lung, bladder, gall bladder, spleen, and pancreas for maternal body, and placenta, amniotic fluid, fetal body, fetal brain, and fetal skeleton. Nonuniform rational B-spline (NURBS) surfaces of each identified region was constructed manually using 3D modeling software. The Hounsfield unit values of each identified organs were gathered from CT images of pregnant patients and converted to tissue density. Organ volumes were further adjusted according to reference measurements for the developing fetus recommended by the World Health Organization (WHO) and International Commission on Radiological Protection. A series of anatomical parameters, including femur length, humerus length, biparietal diameter, abdominal circumference (FAC), and head circumference, were measured and compared with WHO recommendations. The first fetal patient-specific model library was developed with the anatomical characteristics of each model derived from the corresponding patient whose gestational age varies between 8 and 35 weeks. Voxelized models are represented in the form of MCNP matrix input files representing the three-dimensional model of the fetus. The size distributions of each model are also provided in text files. All data are stored on Zenodo and are publicly accessible on the following link: https://zenodo.org/record/6471884. The constructed fetal models and maternal anatomical characteristics are consistent with the corresponding patients. The resulting computational fetus could be used in radiation dosimetry studies to improve the reliability of fetal dosimetry and radiation risks assessment. The advantages of NURBS surfaces in terms of adapting fetal postures and positions enable us to adequately assess their impact on radiation dosimetry calculations.

Estimation of linear and mass attenuation coefficients of soy-lignin bonded Rhizophora spp. particleboard as a potential phantom material using caesium-137 and cobalt-60.

In this study, linear and mass attenuation coefficients of fabricated particleboards intended for use as phantom material were estimated using 137Cs and 60Co radiation sources. Particleboards made of Rhizophora spp. wood trunk bonded with soy flour and lignin were fabricated at a target density of 1.0gcm-3, with and without gloss finish coating. Elemental composition of the particleboards was obtained by means of energy dispersive X-ray (EDX) spectroscopy. Experimental setups were simulated via the GATE Monte Carlo (MC) package, with particle histories of 1 × 106-1 × 107. Linear and mass attenuation coefficients obtained from measurements and GATE simulations were compared and discussed. The percentage differences between the measured and simulated linear and mass attenuation coefficients of the samples were reasonably small (2.05-4.88% for 137Cs and 3.24-5.38% for 60Co). It is shown that all the particleboards have the potential to be used as phantom materials as the attenuation coefficients measured were in good agreement with those of water (calculated with XCOM) and with those simulated with the GATE toolkit. The use of gloss finish coating also did not show any significant effect on the attenuation coefficient of the phantom material. Verification of experimental results via GATE simulations has been shown crucial in providing reliable data for energy transmission studies. Based on the results achieved in this study, it is concluded that the studied material-Rhizophora spp. wood trunk bonded with soy flour and lignin including gloss finish coating-can be used in radiation dosimetry studies.

Development of Fluorinated NP-59: A Revival of Cholesterol Use Imaging with PET.

Imaging of cholesterol use is possible with the 131I scintiscanning/SPECT agent NP-59. This agent provided a noninvasive measure of adrenal function and steroid synthesis. However, iodine isotopes resulted in poor resolution, manufacturing challenges, and high radiation dosimetry to patients that have limited their use and clinical impact. A 18F analog would address these shortcomings while retaining the ability to image cholesterol use. The goal of this study was to prepare and evaluate a 18F analog of NP-59 to serve as a PET imaging agent for functional imaging of the adrenal glands based on cholesterol use. Previous attempts to prepare such an analog of NP-59 have proven elusive. Preclinical and clinical evaluation could be performed once the new fluorine analog of NP-59 production was established. Methods: The recent development of a new reagent for fluorination along with an improved route to the NP-59 precursor allowed for the preparation of a fluorine analog of NP-59, FNP-59. The radiochemistry for the 18F-radiolabeled 18F-FNP-59 is described, and rodent radiation dosimetry studies and invivo imaging in New Zealand rabbits was performed. After invivo toxicity studies, an investigational new drug approval was obtained, and the first-in-humans images with dosimetry using the agent were acquired. Results: In vivo toxicity studies demonstrated that FNP-59 is safe for use at the intended dose. Biodistribution studies with 18F-FNP-59 demonstrated a pharmacokinetic profile similar to that of NP-59 but with decreased radiation exposure. In vivo animal images demonstrated expected uptake in tissues that use cholesterol: gallbladder, liver, and adrenal glands. In this first-in-humans study, subjects had no adverse events and images demonstrated accumulation in target tissues (liver and adrenal glands). Manipulation of uptake was also demonstrated with patients who received cosyntropin, resulting in improved uptake. Conclusion: 18F-FNP-59 provided higher resolution images, with lower radiation dose to the subjects. It has the potential to provide a noninvasive test for patients with adrenocortical diseases.

A portable magnet for radiation biology and dosimetry studies in magnetic fields.

In the current and rapidly evolving era of real-time MRI-guided radiotherapy, our radiation biology and dosimetry knowledge is being tested in a novel way. This paper presents the successful design and implementation of a portable device used to generate strong localized magnetic fields. These are ideally suited for small-scale experiments that mimic the magnetic field environment inside an MRI-linac system, or more broadly MRI-guided particle therapy aswell. A portable permanent magnet-based device employing an adjustable steel yoke and magnetic field focusing cones has been designed, constructed, and tested. The apparatus utilizes two banks of Nd Fe B permanent magnets totaling around 50 kg in mass to generate a strong magnetic field throughout a small volume between two pole tips. The yoke design allows adjustment of the pole tip gap and exchanging of the focusing cones. Further to this, beam portal holes are present in the yoke and focusing cones, allowing for radiation beams of up to 5 5 cm to pass through the region of high magnetic field between the focusing cone tips. Finite element magnetic modeling was performed to design and characterize the performance of the device. Automated physical measurements of the magnetic field components at various locations were measured to confirm the performance. The adjustable pole gap and interchangeable cones allows rapid changing of the experimental set-up to allow different styles of measurements to beperformed. A mostly uniform magnetic field of 1.2 T can be achieved over a volume of at least 3 3 3 cm . This can be reduced in strength to 0.3 T but increased in volume to 10 10 10 cm via removal of the cone tips and/or adjustment of the steel yoke. Although small, these volumes are sufficient to house radiation detectors, cell culture dishes, and various phantom arrangements targeted at examining small radiation field dosimetry inside magnetic field strengths that can be changed with ease. Most important is the ability to align the magnetic field both perpendicular to, or inline with, the radiation beam. To date, the system has been successfully used to conduct published research in the areas of radiation detector performance, lung phantom dosimetry, and how small clinical electron beams behave in these strong magneticfields. A portable, relatively inexpensive, and simple to operate device has successfully been constructed and used for performing radiation oncology studies around the theme of MRI-guided radiotherapy. This can be in either inline and perpendicular magnetic fields of up to 1.2 T with x-ray and particlebeams.

A GPU-accelerated framework for individualized estimation of organ doses in digital tomosynthesis.

Estimation of organ doses in digital tomosynthesis (DT) is challenging due to the lack of existing tools that accurately and flexibly model protocol- and view-specific collimations and motion trajectories of the source and detector for a variety of exam protocols, and the computational inefficiencies of conducting MC simulations. The purpose of this study was to overcome these limitations by developing and benchmarking a GPU-accelerated MC simulation framework compatible with patient-specific computational phantoms for individualized estimation of organ doses in DT. The framework for individualized estimation of dose in DT was developed as a two-step workflow: (1) a custom MATLAB code that accepts a patient-specific computational phantom and exam description (organ markers for defining the extremities of the anatomical region of interest, tube voltage, source-to-image distance, angular sweep range, number of projection views, and the pivot point to image distance - PPID) to compute the field of views (FOVs) for a clinical DT system, and (2) a MC tool (developed using MC-GPU) modeling the configuration of a clinical DT system to estimate organ doses based on the computed FOVs. Using this framework, we estimated organ doses for 28 radiosensitive organs in an adult reference patient model (M; 30 years) imaged using a commercial DT system (VolumeRad, GE Healthcare, Waukesha, WI). The estimates were benchmarked against values from a comparable organ dose estimation framework (reference dataset developed by the Advanced Laboratory for Radiation Dosimetry Studies at University of Florida) for a posterior-anterior chest exam. The resulting differences were quantified as percent relative errors and analyzed to identify any potential sources of bias and uncertainties. The timing performance (run duration in seconds) of the framework was also quantified for the same simulation to gauge the feasibility of the workflow for time-constrained clinical applications. The organ dose estimates from the developed framework showed a close agreement with the reference dataset, with percent relative errors ranging from -6.9% to 5.0% and a mean absolute percent difference of 1.7% over all radiosensitive organs, with the exception of testes and eye lens, for which the percent relative errors were higher at -18.9% and -27.6%, respectively, due to their relative positioning outside the primary irradiation field, leading to fewer photons depositing energy and consequently higher errors in estimated organ doses. The run duration for the same simulation was 916.3 s, representing a substantial improvement in performance over existing nonparallelized MC tools. This study successfully developed and benchmarked a GPU-accelerated framework compatible with patient-specific anthropomorphic computational phantoms for accurate individualized estimation of organ doses in DT. By enabling patient-specific estimation of organ doses, this framework can aid clinicians and researchers by providing them with tools essential for tracking the radiation burden to patients for dose monitoring purposes and identifying the trends and relationships in organ doses for a patient population to optimize existing and develop new exam protocols.

Towards the Establishment of Diagnostic Reference Levels in Saudi Arabia: Review and Opinion

THIS STUDY aims at providing an overview and evaluation of the current situation of the national Diagnostic Reference Levels (DRLs) in Saudi Arabia. Studies published in Pubmed and Google-Scholar, since the DRLs were proposed, are reviewed and general considerations are highlighted, by reviewing some established international DRLs, regarding x-rays and nuclear medicine modalities. The importance of national DRLs (Saudi DRLs) is introduced and discussed. An overview of some studies on Saudi DRLs regarding selected procedures is presented and the validity of radiation dosimetry studies for establishing Saudi DRLs is discussed. The establishment of DRLs for pediatric patient procedures is introduced, discussed and emphasized. An enormous amount of work is required to establish the Saudi DRLs for different procedures, as more than 90% of the work has not been accomplished. Collaboration between researchers is necessary to allow comparisons of DRLs results and to validate the establishment of Saudi DRLs. Furthermore, DRLs for pediatric patient procedures should take priority.

Clinical validation of the novel HDAC6 radiotracer [18F]EKZ-001 in the human brain

PurposeHistone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer’s disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [18F]EKZ-001 ([18F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects.MethodsBiodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT. The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-min dynamic PET/MR scans using a radiometabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a 1-day interscan interval to determine test-retest variability (TRV). Regional volume of distribution (VT) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. VT differences between males and females were evaluated using volume of interest and whole-brain voxel-wise approaches.ResultsThe effective dose was 39.1 ± 7.0 μSv/MBq. Based on the Akaike information criterion, 2TCM was the preferred model compared to 1TCM. Regional LGA VT were in agreement with 2TCM VT, however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional VT values were relatively homogeneous with highest values in the hippocampus and entorhinal cortex. Reduction of acquisition time was achieved with a 0 to 60-min scan followed by a 90 to 120-min scan. Males demonstrated significantly higher VT than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported.Conclusion[18F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with Logan graphical analysis as the preferred quantitative approach. Males showed higher HDAC6 expression across the brain compared to females.

Preclinical pharmacokinetic, biodistribution, radiation dosimetry, and toxicity studies of 99mTc-HYNIC-(Ser)3-LTVPWY: A novel HER2-targeted peptide radiotracer

Accurate assessment of the HER2 expression is an essential issue for predicting response to anti-HER2 therapy in breast cancer patients. The aim of this study was to evaluate 99mTc-HYNIC-(Ser)3-LTVPWY (99mTc-HYNIC-LY) peptide as a novel HER2-targeted radiolabeled peptide in healthy mice to examine the applicability of this imaging agent in a first-in-human clinical trial. To this end, pharmacokinetic and dosimetry studies were performed according to the ICH guideline M3 (R2) with 99mTc-HYNIC-LY. To estimate the radiation-absorbed doses in humans, the accumulated activity in each mouse organ was calculated based on biodistribution data. In addition, toxicology assessment was performed based on mortality events, body weights, and serum biochemical, hematological, and histopathological assays. The pharmacokinetic study showed rapid blood clearance. Based on the results of biodistribution study, the highest radioactivity was observed in the kidneys. The projected absorbed doses to the kidneys, liver, lungs, stomach, and spleen were obtained as 1.70E-02, 1.42E-02, 1.02E-02, 8.62E-03, and 8.34E-03 mSv/MBq, respectively. The results also revealed that serum biochemical and hematological parameters were in the normal range. No significant morphologic alterations were observed in the liver, kidneys, and spleen tissues. Consequently, the results were indicative of the suitability of 99mTc-HYNIC-LY peptide for advancement to a first-in-human clinical trial.

Development of a nonhuman primate computational phantom for radiation dosimetry.

The nonhuman primate (NHP) is an important animal model for evaluating the response of the human body to radiation exposure owing to similarities between its organ structure, genome, life span, and metabolism. However, there is a lack of radiation dosimetry estimations for NHPs. The aim of this work is to construct a computational phantom of NHPs and estimate absorbed fractions and specific absorbed fractions for internal radiation dosimetry. A female rhesus monkey was frozen and sectioned using a cryomacrotome. The transaxial sectioned images were imported into Adobe Photoshop for segmentation of internal organs. A total of 31 organs/tissues were identified and labeled. The segmented voxel phantom was then converted to a boundary representation (BREP) phantom to enable easy alteration of the phantom to mimic monkeys of different stature. The BREP model was then voxelized and imported into the MCNPX Monte Carlo radiation transport code for electron and photon dosimetry calculations. To estimate the appropriateness of using human phantoms as surrogate models for NHPs, absorbed fractions (AFs) and specific absorbed fractions (SAFs) of monoenergetic electrons and photons were calculated and compared with the ICRP reference newborn female phantom and a 1-yr-old female phantom. Considerable differences were observed for both self-absorbed and cross-absorbed doses for some organs between the NHP phantom and newborn phantom. For example, the ratios of the self-absorbed SAF(stomach wall) Monkey to SAF(stomach wall) Newborn ranged from 0.06 at 10keV to 0.29 at 3MeV for photons while the corresponding ratios to cross-absorbed SAF(liver→kidney) Monkey to SAF(liver→kidney) Newborn ranged from 0.78 at 50keV to 5.78 at 10keV for photons. Conversely, values of self-absorbed SAF were much higher (ratios of 2.39-4.19) for the brain and much lower for the uterus (0.51-0.61) in the monkey model compared to the newborn phantom. These dose differences can be attributed to the disparities between organ masses, shapes, and positions between the two phantoms. The developed NHP model can be exploited for the assessment of radiation dose to NHPs in preclinical radiation dosimetry studies and radiation therapy research.

Fluselenamyl: Evaluation of radiation dosimetry in mice and pharmacokinetics in brains of non-human primate

IntroductionTo allow quantitative assessment of therapeutic efficacy for therapeutic interventions (either approved or undergoing FDA approvals) for either inhibiting or reducing development of Aβ pathophysiology in vivo, 18F-labelled tracers, such as Florbetapir, Florbetaben, and Flutemetamol have been approved. Previously, we have reported on development and preclinical validation of 18F-Fluselenamyl, comprising traits of translatable Aβ imaging agents. Herein, we report the dosimetry data for 18F-Fluselenamyl to provide radiation dose deposited within organs and determine effective dose (ED) for human studies, while also evaluating its pharmacokinetics in the nonhuman primate brains. MethodsTo evaluate safety profiles of 18F-Fluselenamyl for enabling its deployment as a PET imaging agent for monitoring Aβ pathophysiology in vivo, we estimated the human radiation dosimetry extrapolated from rodent biodistribution data obtained by standard method of organ dissection. Animal biodistribution studies were performed in FVB/NCR mice (20 males, 20 females), following tail-vein injection of the tracer. Following euthanasia of mice, organs were harvested, counted, radiation dose to each organ and whole body was determined using the standard MIRD methodology. For evaluation of pharmacokinetics in non-human primates, following intravenous injection of the tracer, dynamic PET scan of rhesus monkey brains were performed, and co-registered with MR for anatomical reference. Parametric images of tracer transport rate constant and distribution volume relative to cerebellum were generated using a simplified reference tissue model and a spatially-constraint linear regression algorithm. ResultsThe critical organ in humans has been determined to be the gall bladder with a gender average radiation absorbed dose of 0.079 mGy/MBq with an effective dose of 0.017 mSv/MBq and 0.020 mSv/MBq, in males and females, respectively. Therefore, these data provide preliminary projections on human dosimetry derived from rodent estimates, thereby defining safe imaging conditions for further validations in human subjects. Additionally, the tracer penetrated the non-human primate brain and excreted to background levels at later-time points thus pointing to the potential for high signal/noise ratios during noninvasive imaging. Tissue time activity curves (TACs) also show fast initial uptake with maximum projection of activity at 2–6 min post administration followed by clearance of activity at later time-points from cortex, cerebellum, and white matter of nonhuman primate brain. Parametric images confirmed that the 18F-Fluselenamyl has relative high transport rate constant at striatum, thalamus, and cortex. ConclusionsThe data obtained from radiation dosimetry studies in mice indicate that 18F-Fluselenamyl can be safely used for further evaluation in humans. Additionally, 18F-Fluselenamyl demonstrated ability to traverse the blood brain barrier (BBB) and indicated high initial influx, followed by clearance to background levels in non-human primate brains. Combined information indicates that 18F-Fluselenamyl would be a potential candidate for detecting amyloid plaques in the living human brain.

11C]JNJ54173717, a novel P2X7 receptor radioligand as marker for neuroinflammation: human biodistribution, dosimetry, brain kinetic modelling and quantification of brain P2X7 receptors in patients with Parkinson's disease and healthy volunteers.

The P2X7 receptor (P2X7R) is an ATP-gated ion channel predominantly expressed on activated microglia and is important in neurodegenerative diseases including Parkinson's disease (PD). In this first-in-human study, we investigated [11C]JNJ54173717 ([11C]JNJ717), a selective P2X7R tracer, in healthy volunteers (HV) and PD patients. Biodistribution, dosimetry, kinetic modelling and short-term test-retest variation (TRV), as well as possible genotype effects, were investigated. Biodistribution and radiation dosimetry studies were performed in threeHV (mean age 30 ± 2years, two women) using whole-body PET/CT. The most appropriate kinetic model was determined in 11HV (mean age 62 ± 10years, six women) and 10 PD patients (mean age 64 ± 8years, three women; mean UPDRS motor score 21 ± 8) using 90-min dynamic simultaneous PET/MR scans. The total volume of distribution (VT) was calculated using a one-tissue and a two-tissue compartment model (1TCM, 2TCM) and Logan graphical analysis, and its time stability was assessed. Seven subjects underwent retest scans (mean age 60 ± 13years, fourHV, one woman). A group analysis was performed to compare PD patients and HV. Finally, 13 exons of P2X7R were genotyped in all subjects included in the second part of the study. The mean effective dose was 4.47 ± 0.32μSv/MBq, with the highest absorbed doses to the gallbladder, liver and small intestine. A reversible 2TCM was the most appropriate kinetic model with relatively homogeneous VT values in the grey and white matter. Average VT values were 3.4 ± 0.8 in HV and 3.3 ± 0.7 in PD patients, with no significant difference between the groups, but a possible genotype effect (rs3751143) was identified which can affect VT. Average TRV was 10-15%. The stability of VT over time allowed a reduction in scan time to 70min. [11C]JNJ717 is safe and suitable for quantifying P2X7R expression in human brain. In this pilot study, no significant differences in P2X7R binding were found between HV and PD patients. The results also suggest that genotype effects need to be incorporated in future P2X7R PET analyses.

Dosimetry and Toxicity Studies of the Novel Sulfonamide Derivative of Sulforhodamine 101([18F]SRF101) at a Preclinical Level.

The SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]SRF101) is a Sulforhodamine 101 derivative that was previously synthesised by our group. The fluorescent dye SR101 has been reported as a marker of astroglia in the neocortex of rodents in vivo. The aim of this study was to perform a toxicological evaluation of [18F]SRF101 and to estimate human radiation dosimetry based on preclinical studies. Radiation dosimetry studies were conducted based on biokinetic data obtained from a mouse model. A single-dose toxicity study was carried out. The toxicological limit chosen was <100 μg, and allometric scaling with a safety factor of 100 for unlabelled SRF101 was selected. The absorbed and effective dose estimated using OLINDA/EXM V2.0 for male and female dosimetric models presented the same tendency. The highest total absorbed dose values were for different sections of the intestines. The mean effective dose was 4.03 x10-3 mSv/MBq and 5.08 x10-3 mSv/MBq for the male and female dosimetric models, respectively, using tissue-weighting factors from ICRP-89. The toxicity study detected no changes in the organ or whole-body weight, food consumption, haematologic or clinical chemistry parameters. Moreover, lesions or abnormalities were not found during the histopathological examination. The toxicological evaluation of SRF101 verified the biosafety of the radiotracer for human administration. The dosimetry calculations revealed that the radiation-associated risk of [18F]SRF101 would be of the same order as other 18F radiopharmaceuticals used in clinical applications. These study findings confirm that the novel radiotracer would be safe for use in human PET imaging.

Validation of gallbladder absorbed radiation dose reduction simulation: human dosimetry of [18F]fluortriopride

Background[18F]Fluortriopride (FTP) was developed as a dopamine D3-selective radiotracer, thought to be important to neurobiological reward pathways and implicated in drug addiction, Parkinson’s disease, and schizophrenia. Preclinical radiation dosimetry studies found the gallbladder wall received the highest dose. A gallbladder dose reduction intervention was simulated using a novel reduction model for healthy adults following fatty-meal consumption. The goals of this study were to assess whole body FTP human dosimetry and determine the feasibility of reducing absorbed dose to the gallbladder wall.ResultsEffective dose without a fatty meal was 0.022 ± 0.002 mSv/MBq (± standard deviation) with highest organ dose of 0.436 ± 0.178 mSv/MBq to the gallbladder wall (n = 10). Predicted gallbladder dose reduction with fatty meal consumed was 67.4% (n = 10). Meal consumption by four repeat volunteers decreased average gallbladder dose by 71.3% (n = 4) compared to the original ten volunteers.ConclusionsObserved effective doses were adequately low to continue studying FTP uptake in humans. Validated dosimetry simulations indicate up to a 71% reduction in gallbladder dose can be achieved by employing intrinsic physiology to contract the gallbladder via fatty meal ingestion. This methodology for predicting gallbladder absorbed dose reduction from fatty meal consumption can be applied to other radiopharmaceuticals and radiotherapies.

Evaluation of the UF/NCI hybrid computational phantoms for use in organ dosimetry of pediatric patients undergoing fluoroscopically guided cardiac procedures**This work was supported by Advanced Laboratory for Radiation Dosimetry Studies, University of Florida, American Association of University Women, National Cancer Institute Grant 1F31 CA159464.

Epidemiologic data demonstrate that pediatric patients face a higher relative risk of radiation induced cancers than their adult counterparts at equivalent exposures. Infants and children with congenital heart defects are a critical patient population exposed to ionizing radiation during life-saving procedures. These patients will likely incur numerous procedures throughout their lifespan, each time increasing their cumulative radiation absorbed dose. As continued improvements in long-term prognosis of congenital heart defect patients is achieved, a better understanding of organ radiation dose following treatment becomes increasingly vital. Dosimetry of these patients can be accomplished using Monte Carlo radiation transport simulations, coupled with modern anatomical patient models. The aim of this study was to evaluate the performance of the University of Florida/National Cancer Institute (UF/NCI) pediatric hybrid computational phantom library for organ dose assessment of patients that have undergone fluoroscopically guided cardiac catheterizations. In this study, two types of simulations were modeled. A dose assessment was performed on 29 patient-specific voxel phantoms (taken as representing the patient’s true anatomy), height/weight-matched hybrid library phantoms, and age-matched reference phantoms. Two exposure studies were conducted for each phantom type. First, a parametric study was constructed by the attending pediatric interventional cardiologist at the University of Florida to model the range of parameters seen clinically. Second, four clinical cardiac procedures were simulated based upon internal logfiles captured by a Toshiba Infinix-i Cardiac Bi-Plane fluoroscopic unit. Performance of the phantom library was quantified by computing both the percent difference in individual organ doses, as well as the organ dose root mean square values for overall phantom assessment between the matched phantoms (UF/NCI library or reference) and the patient-specific phantoms. The UF/NCI hybrid phantoms performed at percent differences of between 15% and 30% for the parametric set of irradiation events. Among internal logfile reconstructed procedures, the UF/NCI hybrid phantoms performed with RMS organ dose values between 7% and 29%. Percent improvement in organ dosimetry via the use of hybrid library phantoms over the reference phantoms ranged from 6.6% to 93%. The use of a hybrid phantom library, Monte Carlo radiation transport methods, and clinical information on irradiation events provide a means for tracking organ dose in these radiosensitive patients undergoing fluoroscopically guided cardiac procedures.

68Ga[Ga]-Galmydar: Biodistribution and radiation dosimetry studies in rodents

Introduction68Ga[Ga]-Galmydar is an avid transport substrate of ABCB1 (P-Glycoprotein; 170kDa plasma membrane protein), breast cancer resistance protein (BCRP; ABCG2; 72kDa), penetrates human epidermal carcinoma (KB3-1), breast cancer (MCF7), embryonic kidney (HEK 293) tumor cells and rat cardiomyoblasts, and localizes within the mitochondria of tumor and myocardium cells. 68Ga[Ga]-Galmydar excretes from blood pool quickly, and shows stable retention within rat myocardium in vivo for extended periods, therefore, the agent shows potential to enable myocardial perfusion imaging. The PET tracer also demonstrates ability to probe viability of the blood brain barrier (BBB) in WT mice compared with their mdr1a/1b(−/−) (dKO) and mdr1a/1b/ABCG2(−/−/−) (t-KO) counterparts. Herein, we report dosimetry data for 68Ga[Ga]-Galmydar in mice, and extrapolate that information to determine effective dose (ED) for human studies. MethodsTo further assess safety profiles of 68Ga[Ga]-Galmydar for enabling its deployment as a PET imaging probe for biomedical imaging in vivo, we estimated human radiation dosimetry extrapolated from mice biodistribution data. To accomplish this objective, 68Ga[Ga]-Galmydar was injected intravenously into tails, mice were euthanized, organs harvested (5min, 15min, 30min, 60min, 120min), counted, radiation doses to each organ, and whole body were also determined. ResultsThe effective dose (ED) have been found to be 0.021mGy/MBq in males and 0.023mGy/MBq in females. The highest radiation dose was estimated to the kidneys with a value of 0.17mGy/MBq for males and 0.19mGy/MBq for females with contribution from activity in the urine prior to excretion. The critical organ in humans has been determined to be the gall bladder. These data provide preliminary projections on human dosimetry derived from rodent estimates thus providing platform for further validation of dosimetry analysis in human subjects. ConclusionsCombined data obtained from radiation dosimetry studies in mice indicate that 68Ga[Ga]-Galmydar would be safe for further evaluation of dosimetry toxicity and myocardial perfusion PET imaging in humans.