Search

Background: 177Lu-based radiopharmaceuticals (RPs) are the most used for targeted radionuclide therapy (TRT) due to their good response rates. However, the worldwide availability of 177Lu is limited. 161Tb represents a potential alternative for TRT, as it emits photons for SPECT imaging, β−-particles for therapy, and also releases a significant yield of internal conversion (IE) and Auger electrons (AE). This research aimed to evaluate cell dosimetry with the MIRDcell code considering a realistic localization of three 161Tb- and 177Lu-somatostatin (SST) analogs in different subcellular regions as reported in the literature, various cell cluster sizes (25–1000 µm of radius) and percentage of labeled cells. Experimental values of the α- and β-survival coefficients determined by external beam photon irradiation were used to estimate the survival fraction (SF) of AR42J pancreatic cell clusters and micrometastases. Results: The different localization of RPs labeled with the same radionuclide within the cells, resulted in only slight variations in the dose absorbed by the nuclei (ADN) of the labeled cells with no differences observed in either the unlabeled cells or the SF. ADN of labeled cells (MDLC) produced by 161Tb-RPs were from 2.8–3.7 times higher than those delivered by 177Lu-RPs in cell clusters with a radius lower than 0.1 mm and 10% of labeled cells, due to the higher amount of energy emitted by 161Tb-disintegration in form of IE and AE. However, the 161Tb-RPs/177Lu-RPs MDLC ratio decreased below 1.6 in larger cell clusters (0.5–1 mm) with > 40% labeled cells, due to the significantly higher 177Lu-RPs cross-irradiation contribution. Using a fixed number of disintegrations, SFs of 161Tb-RPs in clusters with > 40% labeled cells were lower than those of 177Lu-RPs, but when the same amount of emitted energy was used no significant differences in SF were observed between 177Lu- and 161Tb-RPs, except for the smallest cluster sizes. Conclusions: Despite the emissions of IE and AE from 161Tb-RPs, their localization within different subcellular regions exerted a negligible influence on the ADN. The same cell damage produced by 177Lu-RPs could be achieved using smaller quantities of 161Tb-RPs, thus making 161Tb a suitable alternative for TRT. [ABSTRACT FROM AUTHOR]

Background: 155Tb represents a potentially useful radionuclide for diagnostic medical applications, but its production remains a challenging problem, in spite of the fact that many production routes have been already investigated and tested. A recent experimental campaign, conducted with low-energy proton beams impinging on a 155Gd target with 91.9% enrichment, demonstrated a significant co-production of 156gTb, a contaminant of great concern since its half-life is comparable to that of 155Tb and its high-energy γ emissions severely impact on the dose released and on the quality of the SPECT images. In the present investigation, the isotopic purity of the enriched 155Gd target necessary to minimize the co-production of contaminant radioisotopes, in particular 156gTb, was explored using various computational simulations. Results: Starting from the recent experimental data obtained with a 91.9% 155Gd-enriched target, the co-production of other Tb radioisotopes besides 155Tb has been theoretically evaluated using the Talys code. It was found that 156Gd, with an isotopic content of 5.87%, was the principal contributor to the co-production of 156gTb. The analysis also demonstrated that the maximum amount of 156Gd admissible for 155Tb production with a radionuclidic purity higher than 99% was 1%. A less stringent condition was obtained through computational dosimetry analysis, suggesting that a 2% content of 156Gd in the target can be tolerated to limit the dose increase to the patient below the 10% limit. Moreover, it has been demonstrated that the imaging properties of the produced 155Tb are not severely affected by this level of impurity in the target. Conclusions: 155Tb can be produced with a quality suitable for medical applications using low-energy proton beams and 155Gd-enriched targets, if the 156Gd impurity content does not exceed 2%. Under these conditions, the dose increase due to the presence of contaminant radioisotopes remains below the 10% limit and good quality images, comparable to those of 111In, are guaranteed. [ABSTRACT FROM AUTHOR]

The cross-sections of the 48Ti(p,x)47Sc, 46cSc, 44mSc, 44gSc, 43Sc, and 48V nuclear reactions were measured from 18 to 70 MeV, with particular attention to 47Sc production. Enriched 48Ti powder was deposited on an aluminum backing and the obtained targets were characterized via elastic backscattering spectroscopy at the INFN-LNL. Targets were exposed to low-intensity proton irradiation using the stacked-foils technique at the ARRONAX facility. Activated samples were measured using γ-spectrometry; the results were compared with the data int he literature and the theoretical TALYS-based values. A regular trend in the new values obtained from the different irradiation runs was noted, as well as a good agreement with the literature data, for all the radionuclides of interest: 47Sc, 46cSc, 44mSc, 44gSc, 43Sc, and 48V. 47Sc production was also discussed, considering yield and radionuclidic purity, for different 47Sc production scenarios. [ABSTRACT FROM AUTHOR]

Background: Manganese is a paramagnetic element suitable for magnetic resonance imaging (MRI) of neuronal function. However, high concentrations of Mn2+ can be neurotoxic. 52gMn may be a valid alternative as positron emission tomography (PET) imaging agent, to obtain information similar to that delivered by MRI but using trace levels of Mn2+, thus reducing its toxicity. Recently, the reaction natV(α,x)52gMn has been proposed as a possible alternative to the standard natCr(p,x)52gMn one, but improvements in the modeling were needed to better compare the two production routes. Purpose: This work focuses on the development of precise simulations and models to compare the 52gMn production from both reactions in terms of amount of activity and radionuclidic purity (RNP), as well as in terms of dose increase (DI) due to the co-produced radioactive contaminants, versus pure 52gMnCl2. Methods: The nuclear code Talys has been employed to optimize the natV(α,x)52gMn cross section by tuning the parameters of the microscopic level densities. Thick-target yields have been calculated from the expression of the rates as energy convolution of cross sections and stopping powers, and finally integrating the time evolution of the relevant decay chains. Dosimetric assessments of [xxMn]Cl2 have been accomplished with OLINDA software 2.2.0 using female and male adult phantoms and biodistribution data for 52gMnCl2 in normal mice. At the end, the yield of xxMn radioisotopes estimated for the two production routes have been combined with the dosimetric results, to assess the DI at different times after the end of the irradiation. Results: Good agreement was obtained between cross-section calculations and measurements.The comparison of the two reaction channels suggests that natV(α,x)52gMn leads to higher yield and higher purity,resulting inmore favorable radiation dosimetry for patients. Conclusions: Both natV(α,x) and natCr(p,x) production routes provide clinically acceptable 52gMnCl2 for PET imaging. However, the natV(α,x)52gMn reaction provides a DI systematically lower than the one obtainable with natCr(p,x)52gMn and a longer time window in which it can be used clinically (RNP ≥ 99%). [ABSTRACT FROM AUTHOR]

Purpose: 64Cu and 67Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of 64Cu is already well established. However, the production of 67Cu in quantities suitable to conduct clinical trials is more challenging as it leads to the coproduction of other Cu isotopes, in particular 64Cu. The aim of this study is to investigate the possibility of using a CuCl2 solution with a mixture of 67/64Cu radioisotopes for therapeutic purposes, providing an alternative solution for the cyclotron production problem. Methods: Copper radioisotopes activities were calculated by considering proton beam irradiation of the following targets: (i) 70Zn in the energy range 70–45 MeV; (ii) 68Zn in the energy range 70–35 MeV; (iii) a combination of 70Zn (70–55 MeV) and 68Zn (55–35 MeV). The contribution of each copper radioisotope to the human‐absorbed dose was estimated with OLINDA/EXM software using the biokinetic model for CuCl2 published by ICRP 53. The total absorbed dose generated by the 67/64CuCl2 mixture, obtained through different production routes, was calculated at different times after the end of the bombardment (EOB). A simple spherical model was used to simulate tumors of different sizes containing uniformly distributed 67/64Cu mixture and to calculate the absorbed dose of self‐irradiation. The biological damage produced by 67Cu and 64Cu was also evaluated through cellular dosimetry and cell surviving fraction assessment using the MIRDcell code, considering two prostate cancer cell lines with different radiosensitivity. Results: The absorbed dose to healthy organs and the effective dose (ED) per unit of administered activity of 67CuCl2 are higher than those of 64CuCl2. Absorbed dose values per unit of administered activity of 67/64CuCl2 mixture increase with time after the EOB because the amount of 67Cu in the mixture increases. Survival data showed that the biological damage caused per each decay of 67Cu is greater than that of 64Cu, assuming that radionuclides remain accumulated in the cell cytoplasm. Sphere model calculations demonstrated that 64Cu administered activity must be about five times higher than that of 67Cu to obtain the same absorbed dose for tumor mass between 0.01 and 10 g and about 10 times higher for very small spheres. Consequently, the 64CuCl2‐absorbed dose to healthy organs will reach higher values than those of 67CuCl2. The supplemental activity of the 67/64CuCl2 mixture, required to get the same tumor‐absorbed dose produced by 67CuCl2, triggers a dose increment (DI) in healthy organs. The waiting time post‐EOB necessary to keep this DI below 10% (t10%) depends on the irradiation methods employed for the production of the 67/64CuCl2 mixture. Conclusions: A mixture of cyclotron produced 67/64Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl2 with minimal DI to healthy organs compared with pure 67Cu. Irradiation of a 70Zn+68Zn target in the 70–35 MeV proton energy range for 185 h appears to be the best option from among all the production routes investigated, as it gives the maximum amount of activity, the shortest t10% (10 h), and less than 1% of 61Cu and 60Cu impurities. [ABSTRACT FROM AUTHOR]

Actinium-225 and other alpha-particle-emitting radionuclides have shown high potential for cancer treatment. Reconstituted high-density lipoproteins (rHDL) specifically recognize the scavenger receptor B type I (SR-BI) overexpressed in several types of cancer cells. Furthermore, after rHDL-SR-BI recognition, the rHDL content is injected into the cell cytoplasm. This research aimed to prepare a targeted 225Ac-delivering nanosystem by encapsulating the radionuclide into rHDL nanoparticles. The synthesis of rHDL was performed in two steps using the microfluidic synthesis method for the subsequent encapsulation of 225Ac, previously complexed to a lipophilic molecule (225Ac-DOTA-benzene-p-SCN, CLog P = 3.42). The nanosystem (13 nm particle size) showed a radiochemical purity higher than 99% and stability in human serum. In vitro studies in HEP-G2 and PC-3 cancer cells (SR-BI positive) demonstrated that 225Ac was successfully internalized into the cytoplasm of cells, delivering high radiation doses to cell nuclei (107 Gy to PC-3 and 161 Gy to HEP-G2 nuclei at 24 h), resulting in a significant decrease in cell viability down to 3.22 ± 0.72% for the PC-3 and to 1.79 ± 0.23% for HEP-G2 at 192 h after 225Ac-rHDL treatment. After intratumoral 225Ac-rHDL administration in mice bearing HEP-G2 tumors, the biokinetic profile showed significant retention of radioactivity in the tumor masses (90.16 ± 2.52% of the injected activity), which generated ablative radiation doses (649 Gy/MBq). The results demonstrated adequate properties of rHDL as a stable carrier for selective deposition of 225Ac within cancer cells overexpressing SR-BI. The results obtained in this research justify further preclinical studies, designed to evaluate the therapeutic efficacy of the 225Ac-rHDL system for targeted alpha-particle therapy of tumors that overexpress the SR-BI receptor. [ABSTRACT FROM AUTHOR]

Purpose: Internal dosimetry has become a very important tool to evaluate the risks and benefits of new endoradiotherapeutic agents. Nowadays, some of the most successful targeted radionuclide therapy (TRT) agents are 177Lu‐DOTA conjugates based on low molecular weight (LMW) Glu‐ureido PSMA inhibitors. It has, however, been demonstrated that the DOTA chelating moiety reduces the internalization of the LMW‐PSMA agent and its radiation dose to the tumor. Previously, we reported that 177Lu‐scFvD2B, an antibody‐based construct, demonstrated statistically significant higher cell uptake and internalization in LNCaP prostate cancer (PCa) cells (PSMA‐positive) when compared to the LMW‐PSMA agents, 177Lu‐PSMA‐617 and 177Lu‐iPSMA, two of the endoradiotherapeutic agents which currently are the most used in PCa therapy. The aim of this study is to estimate the preclinical 177Lu‐scFvD2B organ and tumor‐absorbed doses, and to compare the values with those of 177Lu‐PSMA‐617 and 177Lu‐iPSMA. Methods: 177Lu‐scFvD2B, 177Lu‐PSMA‐617, and 177Lu‐iPSMA were prepared and their radiochemical purity determined. Biodistribution studies of each radiopharmaceutical were then carried out in healthy mice to define the main source organs (SO) and to calculate the number of disintegrations in each source organs per unit of administered activity (NSO). Absorbed dose in the main organs were then calculated for each 177Lu‐conjugate by means of OLINDA/EXM 2.1.1 software, using the calculated NSO for both the adult male and the mouse phantoms as program inputs. Images of mice bearing micropulmonary tumors injected with 177Lu‐conjugates were also obtained. Tumor standardized uptake values (SUV) for the different conjugates, obtained from the 3D SPECT image reconstruction of these mice, were used as the number of disintegrations in a tumor site per unit of administered activity (NT). The tumor‐absorbed dose was calculated using the published electron dose S‐values for sphere models with diameters ranging from 10 µm to 10 mm and considering a uniform activity distribution and tumor density equivalent to water density. Results: All 177Lu‐labeled agents were obtained in high yield (98%). Dosimetric studies carried out using mouse phantoms demonstrated that organ absorbed doses of 177Lu‐scFvD2B were from 1.4 to 2.3 times higher than those for 177Lu‐iPSMA and from 1.5 to 2.6 times higher than those for 177Lu‐PSMA‐617. However, the 177Lu‐scFvD2B values of tumor‐absorbed doses for all investigated tumor sizes were from 2.8 to 3.0 times greater than those calculated for 177Lu‐iPSMA and 177Lu‐PSMA‐617, respectively. Moreover, 177Lu‐scFvD2B showed the highest tumor/kidney ratio when compared to those reported for 177Lu‐albumin conjugates. Conclusions: In this preclinical study, we demonstrated the potential of 177Lu‐scFvD2B as a therapeutic agent for PSMA‐expressing tumors, due to its higher tumor‐absorbed dose when compared with 177Lu‐LMW agents. [ABSTRACT FROM AUTHOR]

Purpose: Technetium‐99m (99mTc) is the radioisotope most widely used in diagnostic nuclear medicine. It is readily available from 99Mo/99mTc generators as the β−decay product of the 99Mo (T½ = 66 h) parent nuclide. This latter is obtained as a fission product in nuclear reactors by neutron‐induced reactions on highly enriched uranium. Alternative production routes, such as direct reactions using proton beams on specific target materials [100Mo(p,2n)99mTc], have the potential to be both reliable and relatively cost‐effective. However, results showed that the 99mTc extracted from proton‐bombarded 100Mo‐enriched targets contains small quantities of several Tc radioisotopes (93mTc, 93Tc, 94Tc, 94mTc, 95Tc, 95mTc, 96Tc, and 97mTc). The aim of this work was to estimate the dose increase (DI) due to the contribution of Tc radioisotopes generated as impurities, after the intravenous injection of four radiopharmaceuticals prepared with cyclotron‐produced 99mTc (CP‐99mTc) using 99.05% 100Mo‐enriched metallic targets. Methods: Four 99mTc radiopharmaceuticals (pertechnetate, sestamibi (MIBI), hexamethylpropylene‐amine oxime (HMPAO) and disodium etidronate (HEDP)) were considered in this study. The biokinetic models reported by the International Commission on Radiological Protection (ICRP) for each radiopharmaceutical were used to define the main source organs and to calculate the number of disintegrations per MBq that occurred in each source organ (Nsource) for each Tc radioisotope present in the CP‐99mTc solution. Then, target organ equivalent doses and effective dose were calculated for each Tc radioisotope with the OLINDA/EXM software versions 1.1 and 2.0, using the calculated Nsource values and the adult male phantom as program inputs. Total effective dose produced by all Tc isotopes impurities present in the CP‐99mTc solution was calculated using the fraction of total activity corresponding to each radioisotope and compared with the effective dose delivered by the generator‐produced 99mTc. Results: In all cases, the total effective DI of CP‐99mTc radiopharmaceuticals calculated with either versions of the OLINDA software was less than 10% from 6 up to 12 h after EOB. 94mTc and 93mTc are the Tc radioisotopes with the highest concentration in the CP‐99mTc solution at EOB. However, their contribution to DI 6 h after EOB is minimal, due to their short half‐lives. The radioisotopes with the largest contribution to the effective DI are 96Tc, followed by 95Tc and 94Tc. This is due to the types of their emissions and relatively long half‐lives, although their concentration in the CP‐99mTc solution is five times lower than that of 94mTc and 93mTc at the EOB. Conclusions: The increase in the radiation dose caused by other Tc radioisotopes contained in CP‐99mTc produced as described here is quite low. Even though the concentrations of the 94Tc and 95Tc radioisotopes in the CP‐99mTc solution exceed the limits established by the European Pharmacopoeia, CP‐99mTc radiopharmaceuticals could be used in routine nuclear medicine diagnostic studies if administered from 6 to 12 h after the EOB, thus maintaining the effective DI within the 10% limit. [ABSTRACT FROM AUTHOR]

The cross-sections of the 48 Ti(p,x) 47 Sc, 46c Sc, 44m Sc, 44g Sc, 43 Sc, and 48 V nuclear reactions were measured from 18 to 70 MeV, with particular attention to 47 Sc production. Enriched 48 Ti powder was deposited on an aluminum backing and the obtained targets were characterized via elastic backscattering spectroscopy at the INFN-LNL. Targets were exposed to low-intensity proton irradiation using the stacked-foils technique at the ARRONAX facility. Activated samples were measured using γ-spectrometry; the results were compared with the data int he literature and the theoretical TALYS-based values. A regular trend in the new values obtained from the different irradiation runs was noted, as well as a good agreement with the literature data, for all the radionuclides of interest: 47 Sc, 46c Sc, 44m Sc, 44g Sc, 43 Sc, and 48 V. 47 Sc production was also discussed, considering yield and radionuclidic purity, for different 47 Sc production scenarios.

Background: Manganese is a paramagnetic element suitable for magnetic resonance imaging (MRI) of neuronal function. However, high concentrations of Mn 2 + can be neurotoxic. 52g Mn may be a valid alternative as positron emission tomography (PET) imaging agent, to obtain information similar to that delivered by MRI but using trace levels of Mn 2 + , thus reducing its toxicity. Recently, the reaction n a t $^{nat}$ V(α,x) 52g Mn has been proposed as a possible alternative to the standard n a t $^{nat}$ Cr(p,x) 52g Mn one, but improvements in the modeling were needed to better compare the two production routes., Purpose: This work focuses on the development of precise simulations and models to compare the 52g Mn production from both reactions in terms of amount of activity and radionuclidic purity (RNP), as well as in terms of dose increase (DI) due to the co-produced radioactive contaminants, versus pure 52g MnCl 2 ., Methods: The nuclear code Talys has been employed to optimize the n a t $^{nat}$ V(α,x) 52g Mn cross section by tuning the parameters of the microscopic level densities. Thick-target yields have been calculated from the expression of the rates as energy convolution of cross sections and stopping powers, and finally integrating the time evolution of the relevant decay chains. Dosimetric assessments of [ x x $^{xx}$ Mn]Cl 2 have been accomplished with OLINDA software 2.2.0 using female and male adult phantoms and biodistribution data for 52g MnCl 2 in normal mice. At the end, the yield of x x $^{xx}$ Mn radioisotopes estimated for the two production routes have been combined with the dosimetric results, to assess the DI at different times after the end of the irradiation., Results: Good agreement was obtained between cross-section calculations and measurements. The comparison of the two reaction channels suggests that n a t $^{nat}$ V(α,x) 52g Mn leads to higher yield and higher purity, resulting in more favorable radiation dosimetry for patients., Conclusions: Both n a t $^{nat}$ V(α,x) and n a t $^{nat}$ Cr(p,x) production routes provide clinically acceptable 52g MnCl 2 for PET imaging. However, the n a t $^{nat}$ V(α,x) 52g Mn reaction provides a DI systematically lower than the one obtainable with n a t $^{nat}$ Cr(p,x) 52g Mn and a longer time window in which it can be used clinically (RNP ≥ 99%)., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

In order to establish the potential of [ 51/52 Mn]Cl 2 as safe PET brain tracers, the radiation effective dose (ED) of [ 51 Mn]- and [ 52 Mn]-chloride has been assessed by using biokinetic models in anthropomorphic phantoms. Results showed that [ 52 Mn]-chloride releases one hundred thirty times more radiation dose (ED = 1.35 mSv/MBq) than [ 51 Mn]-chloride (ED = 1.02E-02 mSv/MBq). Although the maximum positron energy of 52 Mn allows a PET image resolution similar to that of 18 F, activities below 15 MBq should be administered., (Copyright © 2019 Elsevier Ltd. All rights reserved.)