Monte Carlo track-structure for the radionuclide Copper-64: characterization of S-values, nanodosimetry and quantification of direct damage to DNA.

TOPAS-nBio was used to simulate, collision-to-collision, the complete trajectories of electrons in water generated during the explicit simulation of 64Cu decay. S-values and direct damage to the DNA were calculated representing the cell (C) and the cell nucleus (N) with concentric spheres of 5 µm and 4 µm in radius, respectively. The considered 'target'←'source' configurations, including the cell surface (Cs) and cytoplasm (Cy), were: C←C, C←Cs, N←N, N←Cy and N←Cs. Ionization cluster size distributions were also calculated in a cylinder immersed in water corresponding to a DNA segment of 10 base-pairs in length (diameter 2.3 nm, length 3.4 nm), modeling a radioactive point source moving from the central axis to the edge of the cylinder. For that, the first moment (M1) and cumulative probability of having a cluster size of 2 or more ionizations in the cylindrical volume (F2) were obtained. Finally, the direct damage to the DNA was estimated by quantifying double-strand breaks (DSBs) using the clustering algorithm DBSCAN. The S-values obtained with TOPAS-nBio for 64Cu were 7.879 × 10-4 ± 5 × 10-7, 4.351 × 10-4 ± 6 × 10-7, 1.442 × 10-3 ± 1 × 10-6, 2.596 × 10-4 ± 8 × 10-7, 1.127 × 10-4 ± 4 × 10-7 Gy Bq-s-1 for the configurations C←C, C←Cs, N←N, N←Cy and N←Cs, respectively. The difference of these values, compared with previously reported S-values for 64Cu with the code MNCP and software MIRDCell, ranged from -4% to -25% for the configurations N←N and N←Cs, respectively. On the other hand, F2 was maximum with the source at the center of the cylinder 0.373 ± 0.001, and monotonically decreased until reaching a value of 0.058 ± 0.001 at 2.3 nm. The same behavior was observed for M1 with values ranging from 2.188 ± 0.004 to 0.242 ± 0.002. Finally, the DBSCAN algorithm showed that the mean number of DNA DSBs per decay were 0.187 ± 0.001, 0.0317 ± 0.0005, and 0.0125 ± 0.0002 DSB-(Bq-s)-1 for the configurations N←N, N←Cs, and N←Cy, respectively. In conclusion, the results of the S-values show that the absorbed dose strongly depends on the distribution of the radionuclide in the cell, the dose being higher when 64Cu is internalized in the cell nucleus, which is reinforced by the nanodosimetric study by the presence of DNA DSBs attributable to the Auger electrons emitted during the decay of 64Cu.

Positron range effects of 66Ga in small-animal PET imaging.

PURPOSE: Gallium-66 is a non-conventional positron emitter that stands out not only for its high potential to label peptides, proteins and antibodies, but also because it can provide spatio-temporal information of relatively slow physiological processes in the body due to its conveniently long half-life of 9.5 h. However, 66Ga emits the most energetic positrons for PET imaging. The lack of information of the positron range effect on spatial resolution for this positron emitter is an issue, particularly in preclinical imaging. METHODS: The line spread function (LSF) in tissue-equivalent materials with densities between 0.2 and 1.93 g/cm3 was obtained with 66Ga and 18F. A complementary study with the NEMA NU 4-2008 image quality phantom is also included. RESULTS: High-energy positrons moving in lower density materials produce far-reaching activity distributions. The LSFs were characterized with Lorentzian-Gaussian fits, with spatial resolution (FWHM) in the 2.14-3.2 mm range, and long tails extending a few tens of mm depending on the material type and density. A narrowing of the LSF was observed for lung-equivalent materials, indicating the lack of enough material for the positron annihilation to take place. The NEMA NU 4-2008 image quality phantom produced blurred images, notoriously observed in the hot and cold cylinders used for evaluation of recovery coefficients (RC) and spill-over ratios (SOR), producing very low RC and very large SOR. CONCLUSIONS: Quantitative PET imaging with the non-conventional 66Ga is hampered due to the large range of its high-energy positrons affecting both spatial resolution and activity concentration quantification.

A simple and efficient method to recover isotopically enriched Ni-64 from electrolytic solutions.

Production of 64Cu via the proton irradiation of 64Ni, electrodeposited on a suitable backing substrate, remains the most common method to produce this emerging radionuclide. Some unforeseen cases arise when the electrodeposition does not work and the electrolytic solution needs to be reprocessed, but the presence of salt buffers makes it difficult to recover the nickel to prepare a fresh solution. The aim of this work was to develop a simple and efficient method to recover 64Ni from bath solutions.

Transplantation of Human Neural Progenitor Cells (NPC) into Putamina of Parkinsonian Patients: A Case Series Study, Safety and Efficacy Four Years after Surgery.

Individuals with Parkinson's disease (PD) suffer from motor and mental disturbances due to degeneration of dopaminergic and non-dopaminergic neuronal systems. Although they provide temporary symptom relief, current treatments fail to control motor and non-motor alterations or to arrest disease progression. Aiming to explore safety and possible motor and neuropsychological benefits of a novel strategy to improve the PD condition, a case series study was designed for brain grafting of human neural progenitor cells (NPCs) to a group of eight patients with moderate PD. A NPC line, expressing Oct-4 and Sox-2, was manufactured and characterized. Using stereotactic surgery, NPC suspensions were bilaterally injected into patients' dorsal putamina. Cyclosporine A was given for 10 days prior to surgery and continued for 1 month thereafter. Neurological, neuropsychological, and brain imaging evaluations were performed pre-operatively, 1, 2, and 4 years post-surgery. Seven of eight patients have completed 4-year follow-up. The procedure proved to be safe, with no immune responses against the transplant, and no adverse effects. One year after cell grafting, all but one of the seven patients completing the study showed various degrees of motor improvement, and five of them showed better response to medication. PET imaging showed a trend toward enhanced midbrain dopaminergic activity. By their 4-year evaluation, improvements somewhat decreased but remained better than at baseline. Neuropsychological changes were minor, if at all. The intervention appears to be safe. At 4 years post-transplantation we report that undifferentiated NPCs can be delivered safely by stereotaxis to both putamina of patients with PD without causing adverse effects. In 6/7 patients in OFF condition improvement in UPDRS III was observed. PET functional scans suggest enhanced putaminal dopaminergic neurotransmission that could correlate with improved motor function, and better response to L-DOPA. Patients' neuropsychological scores were unaffected by grafting. Trial Registration: Fetal derived stem cells for Parkinson's disease https://doi.org/10.1186/ISRCTN39104513Reg#ISRCTN39104513.

Biodistribution and radiation dosimetry of [64Cu]copper dichloride: first-in-human study in healthy volunteers.

BACKGROUND: In recent years, Copper-64 (T1/2 = 12.7 h) in the chemical form of copper dichloride ([64Cu]CuCl2) has been identified as a potential agent for PET imaging and radionuclide therapy targeting the human copper transporter 1, which is overexpressed in a variety of cancer cells. Limited human biodistribution and radiation dosimetry data is available for this tracer. The aim of this research was to determine the biodistribution and estimate the radiation dosimetry of [64Cu]CuCl2, using whole-body (WB) PET scans in healthy volunteers. Six healthy volunteers were included in this study (3 women and 3 men, mean age ± SD, 54.3 ± 8.6 years; mean weight ± SD, 77.2 ± 12.4 kg). After intravenous injection of the tracer (4.0 MBq/kg), three consecutive WB emission scans were acquired at 5, 30, and 60 min after injection. Additional scans were acquired at 5, 9, and 24 h post-injection. Low-dose CT scan without contrast was used for anatomic localization and attenuation correction. OLINDA/EXM software was used to calculate human radiation doses using the reference adult model. RESULTS: The highest uptake was in the liver, followed by lower and upper large intestine walls, and pancreas, in descending order. Urinary excretion was negligible. The critical organ was liver with a mean absorbed dose of 310 ± 67 µGy/MBq for men and 421 ± 56 µGy/MBq for women, while the mean WB effective doses were 51.2 ± 3.0 and 61.8 ± 5.2 µSv/MBq for men and women, respectively. CONCLUSIONS: To the best of our knowledge, this is the first report on biodistribution and radiation dosimetry of [64Cu]CuCl2 in healthy volunteers. Measured absorbed doses and effective doses are higher than previously reported doses estimated with biodistribution data from patients with prostate cancer, a difference that could be explained not just due to altered biodistribution in cancer patients compared to healthy volunteers but most likely due to the differences in the analysis technique and assumptions in the dose calculation.

Positron range in tissue-equivalent materials: experimental microPET studies.

In this work an experimental investigation was carried out to study the effect that positron range has over positron emission tomography (PET) scans through measurements of the line spread function (LSF) in tissue-equivalent materials. Line-sources consisted of thin capillary tubes filled with (18)F, (13)N or (68)Ga water-solution inserted along the axis of symmetry of cylindrical phantoms constructed with the tissue-equivalent materials: lung (inhale and exhale), adipose tissue, solid water, trabecular and cortical bone. PET scans were performed with a commercial small-animal PET scanner and image reconstruction was carried out with filtered-backprojection. Line-source distributions were analyzed using radial profiles taken on axial slices from which the spatial resolution was determined through the full-width at half-maximum, tenth-maximum, twentieth-maximum and fiftieth-maximum. A double-Gaussian model of the LSFs was used to fit experimental data which can be incorporated into iterative reconstruction methods. In addition, the maximum activity concentration in the line-sources was determined from reconstructed images and compared to the known values for each case. The experimental data indicates that positron range in different materials has a strong effect on both spatial resolution and activity concentration quantification in PET scans. Consequently, extra care should be taken when computing standard-uptake values in PET scans, in particular when the radiopharmaceutical is taken up by different tissues in the body, and more even so with high-energy positron emitters.

Preparation and preclinical evaluation of (66)Ga-DOTA-E(c(RGDfK))2 as a potential theranostic radiopharmaceutical.

INTRODUCTION: Integrin αvß3 plays an important role in angiogenesis and is over-expressed in tumoral endothelial cells and some other tumor cells. RGD (Arg-Gly-Asn) peptides labeled with (68)Ga (t1/2=68min) have showed good characteristics for imaging of αvß3 expression using positron emission tomography (PET). Gallium-66 has been proposed as a PET imaging alternative to (68)Ga and given the unique high energy of its emitted positrons (Emax 4.15MeV) it may also be useful for therapy. The aim of this research is to prepare [(66)Ga]DOTA-E-[c(RGDfK)]2 and evaluate in mice its potential as a new theranostic radiopharmaceutical. METHODS: High specific activity (66)Ga was produced via the (66)Zn(p,n) reaction, and the labelling method of DOTA-E-[c(RGDfK)]2 with (66)Ga was optimized. Radiochemical purity was determined by TLC, and in vitro stability and protein binding were determined. Serial microPET imaging and biodistribution studies were carried out in nude mice bearing C6 xenografts. Radiation absorbed dose estimates were based on the biodistribution studies, where tumor and organs of interest were collected at 0.5, 1, 3, 5 and 24h post-injection of [(66)Ga]DOTA-E-[c(RGDfK)]2. RESULTS: Our results have shown that [(66)Ga]DOTA-E-[c(RGDfK)]2 can be prepared with high radiochemical purity (>97%), specific activity (36-67GBq/µmol), in vitro stability, and moderate protein binding. MicroPET imaging up to 24 post-injection showed contrasting tumors reflecting αvß3-targeted tracer accumulation. Biodistribution studies and dosimetry estimations showed a stable tumor uptake, rapid blood clearance, and favorable tumor-to-tissue ratios. CONCLUSIONS: The peptide conjugated DOTA-E-[c(RGDfK)]2 labeled with (66)Ga may be attractive as a theranostic agent for tumors over-expressing αvß3 integrins.

Very high specific activity 66/68Ga from zinc targets for PET.

This work describes the production of very high specific activity (66/68)Ga from (nat)Zn(p,n) and (66)Zn(p,n) using proton irradiations between 7 and 16 MeV, with emphasis on (66)Ga for use with common bifunctional chelates. Principal radiometallic impurities are (65)Zn from (p,x) and (67)Ga from (p,n). Separation of radiogallium from target material is accomplished with cation exchange chromatography in hydrochloric acid solution. Efficient recycling of Zn target material is possible using electrodeposition of Zn from its chloride form, but these measures are not necessary to achieve high specific activity or near-quantitative radiolabeling yields from natural targets. Inductively coupled plasma mass spectroscopy (ICP-MS) measures less than 2 ppb non-radioactive gallium in the final product, and the reactivity of (66)Ga with common bifunctional chelates, decay corrected to the end of irradiation, is 740 GBq/µmol (20 Ci/µmol) using natural zinc as a target material. Recycling enriched (66)Zn targets increased the reactivity of (66)Ga with common bifunctional chelates.

The use of radiochromic films to measure and analyze the beam profile of charged particle accelerators.

The use of radiochromic films as a simple and inexpensive tool to accurately measure and analyze the beam profile of charged particle accelerators is described. In this study, metallic foils of different materials and thicknesses were irradiated with 17.8MeV protons and autoradiographic images of the beam strike were acquired by exposing pieces of RCF in direct contact with the irradiated foils. The films were digitalized using a conventional scanner and images were analyzed using DoseLab. Beam intensity distributions, isodose curves and linear beam profiles of the digitalized images were acquired.

Niobium sputtered Havar foils for the high-power production of reactive [18F]fluoride by proton irradiation of [18O]H2O targets.

Niobium sputtered Havar entrance foils were used for the production of reactive [(18)F]fluoride by proton irradiation of [(18)O]H(2)O targets under pressurized conditions. The synthesis yield in the routine production of 2-[(18)F]fluoro-2-deoxy-glucose (FDG) was used as an indicative parameter of the reactivity of (18)F. The yield of FDG obtained with (18)F produced in a target with Havar foil was used as a baseline. No statistically significant difference was found in the saturated yields of (18)F when using Havar or Havar-Nb sputtered entrance foils. However, the amount of long-lived radionuclidic impurities decreased more than 10-fold using the Havar-Nb entrance foil. The average decay corrected synthesis yield of FDG, evaluated over a period of more than 2 years, was found to be approximately 5% higher when using a Havar-Nb entrance foil and a marked improvement on the FDG yield consistency was noted. In addition, the frequency of target rebuilding was greatly diminished when using the Nb sputtered entrance foil.

Sustainable production of orphan radionuclides at Wisconsin.

Over a hundred proton-induced reactions have been studied at the University of Wisconsin Medical Physics department since the installation of the first CTI RDS 112 in 1985. The focus has been to measure thick target yields at 11 MeV, in an effort to concentrate on the practical production of positron emitting radionuclides that have favorable decay characteristics, high yields and the potential for labeling pivotal biological tracers. This review covers our recent advances to scale-up the production of the heavy halogens and transition metals as feed-stock for non-conventional PET tracers that are currently attracting increased attention in oncology.

18F-labeled resin microspheres as surrogates for 90Y resin microspheres used in the treatment of hepatic tumors: a radiolabeling and PET validation study.

(90)Y-labeled resin microspheres (SIR-Spheres) are currently used to treat patients with primary and metastatic solid liver tumors. This treatment is typically palliative since patients have exhausted all other standard treatment options. Improving the quality of life and extending patient survival are typical benchmarks for tracking patient response. However, the current method for predicting microsphere biodistributions with (99m)Tc-labeled macroaggregated albumin (MAA) does not correlate well with patient response. This work presents the development of a new (18)F-labeled resin microsphere to serve as a surrogate for the treatment microsphere and to employ the superior resolution and sensitivity of positron emission tomography (PET). The (18)F microsphere biodistributions were determined in a rabbit using PET imaging and histological review. The PET-based uptake ratio was shown to agree with the histological findings to better than 3%. In addition, the radiolabeling process was shown to be rapid, efficient and relatively stable in vivo.