Molecules

Research

14 pages, 926 KiB

Open AccessArticle

Optimization of Cation Exchange for the Separation of Actinium-225 from Radioactive Thorium, Radium-223 and Other Metals

by Jonathan Fitzsimmons, Bryan Foley, Bryna Torre, Megan Wilken, Cathy S. Cutler, Leonard Mausner and Dmitri Medvedev

Molecules 2019, 24(10), 1921; https://doi.org/10.3390/molecules24101921 - 18 May 2019

Cited by 10 | Viewed by 4720

Abstract

Actinium-225 (²²⁵Ac) can be produced with a linear accelerator by proton irradiation of a thorium (Th) target, but the Th also underdoes fission and produces 400 other radioisotopes. No research exists on optimization of the cation step for the purification. The [...] Read more.

Actinium-225 (²²⁵Ac) can be produced with a linear accelerator by proton irradiation of a thorium (Th) target, but the Th also underdoes fission and produces 400 other radioisotopes. No research exists on optimization of the cation step for the purification. The research herein examines the optimization of the cation exchange step for the purification of ²²⁵Ac. The following variables were tested: pH of load solution (1.5–4.6); rinse steps with various concentrations of HCl, HNO₃, H₂SO₄, and combinations of HCl and HNO₃; various thorium chelators to block retention; MP50 and AG50 resins; and retention of 20–45 elements with different rinse sequences. The research indicated that HCl removes more isotopes earlier than HNO₃, but that some elements, such as barium and radium, could be eluted with ≥2.5 M HNO₃. The optimal pH of the load solution was 1.5–2.0, and the optimized rinse sequence was five bed volumes (BV) of 1 M citric acid pH 2.0, 3 BV of water, 3 BV of 2 M HNO₃, 6 BV of 2.5 M HNO₃ and 20 BV of 6 M HNO₃. The sequence recovered >90% of ²²⁵Ac with minimal ²²³Ra and thorium present. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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24 pages, 5413 KiB

Open AccessArticle

Preparation of Zirconium-89 Solutions for Radiopharmaceutical Purposes: Interrelation Between Formulation, Radiochemical Purity, Stability and Biodistribution

by Anton Larenkov, Victor Bubenschikov, Artur Makichyan, Maria Zhukova, Alina Krasnoperova and Galina Kodina

Molecules 2019, 24(8), 1534; https://doi.org/10.3390/molecules24081534 - 18 Apr 2019

Cited by 19 | Viewed by 5475

Abstract

Zirconium-89 is a promising radionuclide for nuclear medicine. The aim of the present work was to find a suitable method for obtaining zirconium-89 solutions for radiopharmaceutical purposes. For this purpose, the ion exchange behavior of zirconium-89 solutions was studied. Radio-TLC (thin layer chromatography) [...] Read more.

Zirconium-89 is a promising radionuclide for nuclear medicine. The aim of the present work was to find a suitable method for obtaining zirconium-89 solutions for radiopharmaceutical purposes. For this purpose, the ion exchange behavior of zirconium-89 solutions was studied. Radio-TLC (thin layer chromatography) and biodistribution studies were carried out to understand speciation of zirconium-89 complexes and their role in the development of new radiopharmaceuticals. Three methods of zirconium-89 isolation were studied using ZR (hydroxamate) and Chelex-100 resins. It was found that ZR-resin alone is not enough to obtain stable zirconium-89 formulations. An easy and effective method of reconstitution of [⁸⁹Zr]Zr-oxalate to [⁸⁹Zr]Zr-citrate using Chelex-100 resin was developed. Developed procedures allow obtaining [⁸⁹Zr]Zr-oxalate (in 0.1 M sodium oxalate solution) and [⁸⁹Zr]Zr-citrate (in 0.1–1.0 M sodium citrate solution). These solutions are perfectly suitable and convenient for radiopharmaceutical purposes. Our results prove [⁸⁹Zr]Zr-citrate to be advantageous over [⁸⁹Zr]Zr-oxalate. During evaluation of speciation of zirconium-89 complexes, a new TLC method was developed, since it was proved that there is no comprehensive method for analysis or zirconium-89 preparations. The new method provides valuable insights about the content of “active” ionic form of zirconium-89. The interrelation of the chromatographic behavior of zirconium-89 preparations and their biodistribution was studied. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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10 pages, 1535 KiB

Open AccessArticle

Defining Processing Times for Accelerator Produced ²²⁵Ac and Other Isotopes from Proton Irradiated Thorium

by Jonathan Fitzsimmons, Justin Griswold, Dmitri Medvedev, Cathy S. Cutler and Leonard Mausner

Molecules 2019, 24(6), 1095; https://doi.org/10.3390/molecules24061095 - 20 Mar 2019

Cited by 12 | Viewed by 4955

Abstract

During the purification of radioisotopes, decay periods or time dependent purification steps may be required to achieve a certain level of radiopurity in the final product. Actinum-225 (Ac-225), Silver-111 (Ag-111), Astatine-211 (At-211), Ruthenium-105 (Ru-105), and Rhodium-105 (Rh-105) are produced in a high energy [...] Read more.

During the purification of radioisotopes, decay periods or time dependent purification steps may be required to achieve a certain level of radiopurity in the final product. Actinum-225 (Ac-225), Silver-111 (Ag-111), Astatine-211 (At-211), Ruthenium-105 (Ru-105), and Rhodium-105 (Rh-105) are produced in a high energy proton irradiated thorium target. Experimentally measured cross sections, along with MCNP6-generated cross sections, were used to determine the quantities of Ac-225, Ag-111, At-211, Ru-105, Rh-105, and other co-produced radioactive impurities produced in a proton irradiated thorium target at Brookhaven Linac Isotope Producer (BLIP). Ac-225 and Ag-111 can be produced with high radiopurity by the proton irradiation of a thorium target at BLIP. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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11 pages, 1235 KiB

Open AccessArticle

Comparing Gly¹¹/dAla¹¹-Replacement vs. the in-Situ Neprilysin-Inhibition Approach on the Tumor-targeting Efficacy of the ¹¹¹In-SB3/¹¹¹In-SB4 Radiotracer Pair

by Emmanouil Lymperis, Aikaterini Kaloudi, Panagiotis Kanellopoulos, Marion de Jong, Eric P. Krenning, Berthold A. Nock and Theodosia Maina

Molecules 2019, 24(6), 1015; https://doi.org/10.3390/molecules24061015 - 13 Mar 2019

Cited by 10 | Viewed by 2930

Abstract

Background: The GRPR-antagonist ⁶⁸Ga-SB3 visualized prostate cancer lesions in animal models and in patients. Switching radiometal from ⁶⁸Ga to ¹¹¹In impaired tumor targeting in mice, but coinjection of the neprilysin (NEP)-inhibitor phosphoramidon (PA) stabilized ¹¹¹In-SB3 in circulation and [...] Read more.

Background: The GRPR-antagonist ⁶⁸Ga-SB3 visualized prostate cancer lesions in animal models and in patients. Switching radiometal from ⁶⁸Ga to ¹¹¹In impaired tumor targeting in mice, but coinjection of the neprilysin (NEP)-inhibitor phosphoramidon (PA) stabilized ¹¹¹In-SB3 in circulation and remarkably increased tumor uptake. We herein report on the biological profile of ¹¹¹In-SB4: ¹¹¹In-[dAla¹¹]SB3. Methods: The biological responses of ¹¹¹In-SB3/SB4 were compared in PC-3 cells and animal models. Results: Gly¹¹/dAla¹¹-replacement deteriorated GRPR-affinity (SB4 IC₅₀: 10.7 ± 0.9 nM vs. SB3 IC₅₀: 4.6 ± 0.3 nM) and uptake in PC-3 cells (¹¹¹In-SB4: 1.3 ± 0.4% vs. ¹¹¹In-SB3 16.2 ± 0.8% at 1 h). ¹¹¹In-SB4 was more stable than ¹¹¹In-SB3, but PA-coinjection stabilized both radiotracers in peripheral mice blood. Unmodified ¹¹¹In-SB3 showed higher uptake in PC-3 xenografts (8.8 ± 3.0%ID/g) vs. ¹¹¹In-SB4 (3.1 ± 1.1%ID/g) at 4 h pi. PA-coinjection improved tumor uptake, with ¹¹¹In-SB3 still showing superior tumor targeting (38.3 ± 7.9%ID/g vs. 7.4 ± 0.3%ID/g for ¹¹¹In-SB4). Conclusions: Replacement of Gly¹¹ by dAla¹¹ improved in vivo stability, however, at the cost of GRPR-affinity and cell uptake, eventually translating into inferior tumor uptake of ¹¹¹In-SB4 vs. unmodified ¹¹¹In-SB3. On the other hand, in-situ NEP-inhibition turned out to be a more efficient and direct strategy to optimize the in vivo profile of ¹¹¹In-SB3, and potentially other peptide radiotracers. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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19 pages, 2321 KiB

Open AccessArticle

Development of a Potential Gallium-68-Labelled Radiotracer Based on DOTA-Curcumin for Colon-Rectal Carcinoma: From Synthesis to In Vivo Studies

by Giulia Orteca, Federica Pisaneschi, Sara Rubagotti, Tracy W. Liu, Giacomo Biagiotti, David Piwnica-Worms, Michele Iori, Pier Cesare Capponi, Erika Ferrari and Mattia Asti

Molecules 2019, 24(3), 644; https://doi.org/10.3390/molecules24030644 - 12 Feb 2019

Cited by 11 | Viewed by 3899

Abstract

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell [...] Read more.

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative (⁶⁸Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. ⁶⁸Ga-DOTA-C21 exhibits decent stability (57 ± 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 ± 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of ⁶⁸Ga-DOTA-C21 is 3.57 ± 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 ± 0.2. High amount of activity (12.73 ± 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 ± 3.3% ID/g), lungs (8.42 ± 0.8% ID/g), liver (5.81 ± 0.5% ID/g) and heart (4.70 ± 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, ⁶⁸Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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14 pages, 2403 KiB

Open AccessArticle

Therapeutic Radiometals: Worldwide Scientific Literature Trend Analysis (2008–2018)

by Licia Uccelli, Petra Martini, Corrado Cittanti, Aldo Carnevale, Loretta Missiroli, Melchiore Giganti, Mirco Bartolomei and Alessandra Boschi

Molecules 2019, 24(3), 640; https://doi.org/10.3390/molecules24030640 - 12 Feb 2019

Cited by 22 | Viewed by 4321 | Correction

Abstract

Academic journals have published a large number of papers in the therapeutic nuclear medicine (NM) research field in the last 10 years. Despite this, a literature analysis has never before been made to point out the research interest in therapeutic radionuclides (RNs). For [...] Read more.

Academic journals have published a large number of papers in the therapeutic nuclear medicine (NM) research field in the last 10 years. Despite this, a literature analysis has never before been made to point out the research interest in therapeutic radionuclides (RNs). For this reason, the present study aims specifically to analyze the research output on therapeutic radiometals from 2008 to 2018, with intent to quantify and identify global trends in scientific literature and emphasize the interdisciplinary nature of this research field. The data search targeted conventional (¹³¹I, ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁸Re, ¹⁸⁶Re, ¹⁵³Sm, ⁸⁹Sr, ¹⁸⁶Er) and emergent (⁶⁷Cu, ⁴⁷Sc, ²²³Ra, ¹⁶⁶Ho, ¹⁶¹Tb, ¹⁴⁹Tb, ²¹²Pb/²¹²Bi, ²²⁵Ac, ²¹³Bi, ²¹¹At, ^117mSn) RNs. Starting from this time frame, authors have analyzed and interpreted this scientific trend quantitatively first, and qualitatively after. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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13 pages, 2297 KiB

Open AccessArticle

Dosimetry of ¹⁷⁷Lu-PSMA-617 after Mannitol Infusion and Glutamate Tablet Administration: Preliminary Results of EUDRACT/RSO 2016-002732-32 IRST Protocol

by Anna Sarnelli, Maria Luisa Belli, Valentina Di Iorio, Emilio Mezzenga, Monica Celli, Stefano Severi, Elisa Tardelli, Silvia Nicolini, Devil Oboldi, Licia Uccelli, Corrado Cittanti, Manuela Monti, Mahila Ferrari and Giovanni Paganelli

Molecules 2019, 24(3), 621; https://doi.org/10.3390/molecules24030621 - 11 Feb 2019

Cited by 35 | Viewed by 4747

Abstract

Radio-ligand therapy (RLT) with¹⁷⁷Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate-cancer (mCRPC). A prospective phase-II study (EUDRACT/RSO,2016-002732-32) on mCRPC is ongoing at IRST (Meldola, Italy). A total of 9 patients (median age: 68 y, range: 53–85) were enrolled [...] Read more.

Radio-ligand therapy (RLT) with¹⁷⁷Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate-cancer (mCRPC). A prospective phase-II study (EUDRACT/RSO,2016-002732-32) on mCRPC is ongoing at IRST (Meldola, Italy). A total of 9 patients (median age: 68 y, range: 53–85) were enrolled for dosimetry evaluation of parotid glands (PGs), kidneys, red marrow (RM) and whole body (WB). Folic polyglutamate tablets were orally administered as PGs protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake. The whole body planar image (WBI) and blood samples were acquired at different times post infusion (1 h, 16–24 h, 36–48 h and 120 h). Dose calculation was performed with MIRD formalism (OLINDA/EXM software). The median effective half-life was 33.0 h (range: 25.6–60.7) for PGs, 31.4 h (12.2–80.6) for kidneys, 8.2 h (2.5–14.7) for RM and 40.1 h (31.6–79.7) for WB. The median doses were 0.48 mGy/MBq (range: 0.33–2.63) for PGs, 0.70 mGy/MBq (0.26–1.07) for kidneys, 0.044 mGy/MBq (0.023–0.067) for RM and 0.04 mGy/MBq (0.02–0.11) for WB. A comparison with previously published dosimetric data was performed and a significant difference was found for PGs while no significant difference was observed for the kidneys. For PGs, the possibility of reducing uptake by administering glutamate tablets during RLT seems feasible while further research is warranted for a more focused evaluation of the reduction in kidney uptake. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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22 pages, 6529 KiB

Open AccessArticle

Innovative Target for Production of Technetium-99m by Biomedical Cyclotron

by Hanna Skliarova, Sara Cisternino, Gianfranco Cicoria, Mario Marengo and Vincenzo Palmieri

Molecules 2019, 24(1), 25; https://doi.org/10.3390/molecules24010025 - 21 Dec 2018

Cited by 20 | Viewed by 6250

Abstract

Technetium-99m (^99mTc) is the most used radionuclide worldwide in nuclear medicine for diagnostic imaging procedures. ^99mTc is typically extracted from portable generators containing ⁹⁹Mo, which is produced normally in nuclear reactors as a fission product of highly enriched Uranium [...] Read more.

Technetium-99m (^99mTc) is the most used radionuclide worldwide in nuclear medicine for diagnostic imaging procedures. ^99mTc is typically extracted from portable generators containing ⁹⁹Mo, which is produced normally in nuclear reactors as a fission product of highly enriched Uranium material. Due to unexpected outages or planned and unplanned reactor shutdown, significant ^99mTc shortages appeared as a problem since 2008 The alternative cyclotron-based approach through the ¹⁰⁰Mo(p,2n)^99mTc reaction is considered one of the most promising routes for direct ^99mTc production in order to mitigate potential ⁹⁹Mo shortages. The design and manufacturing of appropriate cyclotron targets for the production of significant amounts of a radiopharmaceutical for medical use is a technological challenge. In this work, a novel solid target preparation method was developed, including sputter deposition of a dense, adherent, and non-oxidized Mo target material onto a complex backing plate. The latter included either chemically resistant sapphire or synthetic diamond brazed in vacuum conditions to copper. The target thermo-mechanical stability tests were performed under 15.6 MeV proton energy and different beam intensities, up to the maximum provided by the available GE Healthcare (Chicago, IL, USA) PET trace medical cyclotron. The targets resisted proton beam currents up to 60 µA (corresponding to a heat power density of about 1 kW/cm²) without damage or Mo deposited layer delamination. The chemical stability of the proposed backing materials was proven by gamma-spectroscopy analysis of the solution obtained after the standard dissolution procedure of irradiated targets in H₂O₂. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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13 pages, 2477 KiB

Open AccessArticle

A Flexible Synthesis of ⁶⁸Ga-Labeled Carbonic Anhydrase IX (CAIX)-Targeted Molecules via CBT/1,2-Aminothiol Click Reaction

by Kuo-Ting Chen, Kevin Nguyen, Christian Ieritano, Feng Gao and Yann Seimbille

Molecules 2019, 24(1), 23; https://doi.org/10.3390/molecules24010023 - 21 Dec 2018

Cited by 24 | Viewed by 5709

Abstract

We herein describe a flexible synthesis of a small library of ⁶⁸Ga-labeled CAIX-targeted molecules via an orthogonal 2-cyanobenzothiazole (CBT)/1,2-aminothiol click reaction. Three novel CBT-functionalized chelators (1–3) were successfully synthesized and labeled with the positron emitter gallium-68. Cross-ligation between [...] Read more.

We herein describe a flexible synthesis of a small library of ⁶⁸Ga-labeled CAIX-targeted molecules via an orthogonal 2-cyanobenzothiazole (CBT)/1,2-aminothiol click reaction. Three novel CBT-functionalized chelators (1–3) were successfully synthesized and labeled with the positron emitter gallium-68. Cross-ligation between the pre-labeled bifunctional chelators (BFCs) and the 1,2-aminothiol-acetazolamide derivatives (8 and 9) yielded six new ⁶⁸Ga-labeled CAIX ligands with high radiochemical yields. The click reaction conditions were optimized to improve the reaction rate for applications with short half-life radionuclides. Overall, our methodology allows for a simple and efficient radiosynthetic route to produce a variety of ⁶⁸Ga-labeled imaging agents for tumor hypoxia. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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15 pages, 2023 KiB

Open AccessArticle

Radiobiological Characterization of ⁶⁴CuCl₂ as a Simple Tool for Prostate Cancer Theranostics

by Joana Fernandes Guerreiro, Vítor Alves, Antero José Abrunhosa, António Paulo, Octávia Monteiro Gil and Filipa Mendes

Molecules 2018, 23(11), 2944; https://doi.org/10.3390/molecules23112944 - 11 Nov 2018

Cited by 17 | Viewed by 4327

Abstract

⁶⁴CuCl₂ has recently been proposed as a promising agent for prostate cancer (PCa) theranostics, based on preclinical studies in cellular and animal models, and on the increasing number of human studies documenting its use for PCa diagnosis. Nevertheless, the use of [...] Read more.

⁶⁴CuCl₂ has recently been proposed as a promising agent for prostate cancer (PCa) theranostics, based on preclinical studies in cellular and animal models, and on the increasing number of human studies documenting its use for PCa diagnosis. Nevertheless, the use of ⁶⁴CuCl₂ raises important radiobiological questions that have yet to be addressed. In this work, using a panel of PCa cell lines in comparison with a non-tumoral prostate cell line, we combined cytogenetic approaches with radiocytotoxicity assays to obtain significant insights into the cellular consequences of exposure to ⁶⁴CuCl₂. PCa cells were found to exhibit increased ⁶⁴CuCl₂ uptake, which could not be attributed to increased expression of the main copper cellular importer, hCtr1, as had been previously suggested. Early DNA damage and genomic instability were also higher in PCa cells, with the tumoral cell lines exhibiting deficient DNA-damage repair upon exposure to ⁶⁴CuCl₂. This was corroborated by the observation that ⁶⁴CuCl₂ was more cytotoxic in PCa cells than in non-tumoral cells. Overall, we showed for the first time that PCa cells had a higher sensitivity to ⁶⁴CuCl₂ than healthy cells, supporting the idea that this compound deserved to be further evaluated as a theranostic agent in PCa. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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13 pages, 1666 KiB

Open AccessArticle

⁶⁶Ga: A Novelty or a Valuable Preclinical Screening Tool for the Design of Targeted Radiopharmaceuticals?

by Alejandro Amor-Coarasa, James M. Kelly, Shashikanth Ponnala, Anastasia Nikolopoulou, Clarence Williams, Jr. and John W. Babich

Molecules 2018, 23(10), 2575; https://doi.org/10.3390/molecules23102575 - 9 Oct 2018

Cited by 10 | Viewed by 3536

Abstract

Emerging interest in extending the plasma half-life of small molecule radioligands warrants a consideration of the appropriate radionuclide for PET imaging at longer time points (>8 h). Among candidate positron-emitting radionuclides, ⁶⁶Ga (t_1/2 = 9.5 h, β+ = 57%) has suitable [...] Read more.

Emerging interest in extending the plasma half-life of small molecule radioligands warrants a consideration of the appropriate radionuclide for PET imaging at longer time points (>8 h). Among candidate positron-emitting radionuclides, ⁶⁶Ga (t_1/2 = 9.5 h, β+ = 57%) has suitable nuclear and chemical properties for the labeling and PET imaging of radioligands of this profile. We investigated the value of ⁶⁶Ga to preclinical screening and the evaluation of albumin-binding PSMA-targeting small molecules. ⁶⁶Ga was produced by irradiation of a ^natZn target. ⁶⁶Ga³⁺ ions were separated from Zn²⁺ ions by an optimized UTEVA anion exchange column that retained 99.99987% of Zn²⁺ ions and allowed 90.2 ± 2.8% recovery of ⁶⁶Ga³⁺. Three ligands were radiolabeled in 46.4 ± 20.5%; radiochemical yield and >90% radiochemical purity. Molar activity was 632 ± 380 MBq/µmol. Uptake in the tumor and kidneys at 1, 3, 6, and 24 h p.i. was determined by µPET/CT imaging and more completely predicted the distribution kinetics than uptake of the [⁶⁸Ga]Ga-labeled ligands did. Although there are multiple challenges to the use of ⁶⁶Ga for clinical PET imaging, it can be a valuable research tool for ligand screening and preclinical imaging beyond 24 h. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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12 pages, 8133 KiB

Open AccessArticle

Early Evaluation of Copper Radioisotope Production at ISOLPHARM

by Francesca Borgna, Michele Ballan, Chiara Favaretto, Marco Verona, Marianna Tosato, Michele Caeran, Stefano Corradetti, Alberto Andrighetto, Valerio Di Marco, Giovanni Marzaro and Nicola Realdon

Molecules 2018, 23(10), 2437; https://doi.org/10.3390/molecules23102437 - 24 Sep 2018

Cited by 18 | Viewed by 4766

Abstract

The ISOLPHARM (ISOL technique for radioPHARMaceuticals) project is dedicated to the development of high purity radiopharmaceuticals exploiting the radionuclides producible with the future Selective Production of Exotic Species (SPES) Isotope Separation On-Line (ISOL) facility at the Legnaro National Laboratories of the Italian National [...] Read more.

The ISOLPHARM (ISOL technique for radioPHARMaceuticals) project is dedicated to the development of high purity radiopharmaceuticals exploiting the radionuclides producible with the future Selective Production of Exotic Species (SPES) Isotope Separation On-Line (ISOL) facility at the Legnaro National Laboratories of the Italian National Institute for Nuclear Physics (INFN-LNL). At SPES, a proton beam (up to 70 MeV) extracted from a cyclotron will directly impinge a primary target, where the produced isotopes are released thanks to the high working temperatures (2000 °C), ionized, extracted and accelerated, and finally, after mass separation, only the desired nuclei are collected on a secondary target, free from isotopic contaminants that decrease their specific activity. A case study for such project is the evaluation of the feasibility of the ISOL production of ⁶⁴Cu and ⁶⁷Cu using a zirconium germanide target, currently under development. The producible activities of ⁶⁴Cu and ⁶⁷Cu were calculated by means of the Monte Carlo code FLUKA, whereas dedicated off-line tests with stable beams were performed at LNL to evaluate the capability to ionize and recover isotopically pure copper. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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19 pages, 6498 KiB

Open AccessArticle

14 MeV Neutrons for ⁹⁹Mo/^99mTc Production: Experiments, Simulations and Perspectives

by Marco Capogni, Antonino Pietropaolo, Lina Quintieri, Maurizio Angelone, Alessandra Boschi, Mauro Capone, Nadia Cherubini, Pierino De Felice, Alessandro Dodaro, Adriano Duatti, Aldo Fazio, Stefano Loreti, Petra Martini, Guglielmo Pagano, Micol Pasquali, Mario Pillon, Licia Uccelli and Aldo Pizzuto

Molecules 2018, 23(8), 1872; https://doi.org/10.3390/molecules23081872 - 27 Jul 2018

Cited by 33 | Viewed by 7072

Abstract

Background: the gamma-emitting radionuclide Technetium-99m (^99mTc) is still the workhorse of Single Photon Emission Computed Tomography (SPECT) as it is used worldwide for the diagnosis of a variety of phatological conditions. ^99mTc is obtained from ⁹⁹Mo/^99mTc generators [...] Read more.

Background: the gamma-emitting radionuclide Technetium-99m (^99mTc) is still the workhorse of Single Photon Emission Computed Tomography (SPECT) as it is used worldwide for the diagnosis of a variety of phatological conditions. ^99mTc is obtained from ⁹⁹Mo/^99mTc generators as pertechnetate ion, which is the ubiquitous starting material for the preparation of ^99mTc radiopharmaceuticals. ⁹⁹Mo in such generators is currently produced in nuclear fission reactors as a by-product of ²³⁵U fission. Here we investigated an alternative route for the production of ⁹⁹Mo by irradiating a natural metallic molybdenum powder using a 14-MeV accelerator-driven neutron source. Methods: after irradiation, an efficient isolation and purification of the final ^99mTc-pertechnetate was carried out by means of solvent extraction. Monte Carlo simulations allowed reliable predictions of ⁹⁹Mo production rates for a newly designed 14-MeV neutron source (New Sorgentina Fusion Source). Results: in traceable metrological conditions, a level of radionuclidic purity consistent with accepted pharmaceutical quality standards, was achieved. Conclusions: we showed that this source, featuring a nominal neutron emission rate of about 10¹⁵ s⁻¹, may potentially supply an appreciable fraction of the current ⁹⁹Mo global demand. This study highlights that a robust and viable solution, alternative to nuclear fission reactors, can be accomplished to secure the long-term supply of ⁹⁹Mo. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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Review

Jump to: Research, Other

29 pages, 1765 KiB

Open AccessReview

A Step-by-Step Guide for the Novel Radiometal Production for Medical Applications: Case Studies with ⁶⁸Ga, ⁴⁴Sc, ¹⁷⁷Lu and ¹⁶¹Tb

by Zeynep Talip, Chiara Favaretto, Susanne Geistlich and Nicholas P. van der Meulen

Molecules 2020, 25(4), 966; https://doi.org/10.3390/molecules25040966 - 20 Feb 2020

Cited by 46 | Viewed by 9597

Abstract

The production of novel radionuclides is the first step towards the development of new effective radiopharmaceuticals, and the quality thereof directly affects the preclinical and clinical phases. In this review, novel radiometal production for medical applications is briefly elucidated. The production status of [...] Read more.

The production of novel radionuclides is the first step towards the development of new effective radiopharmaceuticals, and the quality thereof directly affects the preclinical and clinical phases. In this review, novel radiometal production for medical applications is briefly elucidated. The production status of the imaging nuclide ⁴⁴Sc and the therapeutic β^--emitter nuclide ¹⁶¹Tb are compared to their more established counterparts, ⁶⁸Ga and ¹⁷⁷Lu according to their targetry, irradiation process, radiochemistry, and quality control aspects. The detailed discussion of these significant issues will help towards the future introduction of these promising radionuclides into drug manufacture for clinical application under Good Manufacturing Practice (GMP). Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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17 pages, 3798 KiB

Open AccessReview

Perspectives on the Use of Liquid Extraction for Radioisotope Purification

by Petra Martini, Andrea Adamo, Neilesh Syna, Alessandra Boschi, Licia Uccelli, Nopphon Weeranoppanant, Jack Markham and Giancarlo Pascali

Molecules 2019, 24(2), 334; https://doi.org/10.3390/molecules24020334 - 18 Jan 2019

Cited by 22 | Viewed by 6226

Abstract

The reliable and efficient production of radioisotopes for diagnosis and therapy is becoming an increasingly important capability, due to their demonstrated utility in Nuclear Medicine applications. Starting from the first processes involving the separation of ^99mTc from irradiated materials, several methods and [...] Read more.

The reliable and efficient production of radioisotopes for diagnosis and therapy is becoming an increasingly important capability, due to their demonstrated utility in Nuclear Medicine applications. Starting from the first processes involving the separation of ^99mTc from irradiated materials, several methods and concepts have been developed to selectively extract the radioisotopes of interest. Even though the initial methods were based on liquid-liquid extraction (LLE) approaches, the perceived difficulty in automating such processes has slowly moved the focus towards resin separation methods, whose basic chemical principles are often similar to the LLE ones in terms of chelators and phases. However, the emerging field of flow chemistry allows LLE to be easily automated and operated in a continuous manner, resulting in an even improved efficiency and reliability. In this contribution, we will outline the fundamentals of LLE processes and their translation into flow-based apparatuses; in addition, we will provide examples of radioisotope separations that have been achieved using LLE methods. This article is intended to offer insights about the future potential of LLE to purify medically relevant radioisotopes. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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14 pages, 10722 KiB

Open AccessLetter

LARAMED: A Laboratory for Radioisotopes of Medical Interest

by Juan Esposito, Diego Bettoni, Alessandra Boschi, Michele Calderolla, Sara Cisternino, Giovanni Fiorentini, Giorgio Keppel, Petra Martini, Mario Maggiore, Liliana Mou, Micòl Pasquali, Lorenzo Pranovi, Gaia Pupillo, Carlos Rossi Alvarez, Lucia Sarchiapone, Gabriele Sciacca, Hanna Skliarova, Paolo Favaron, Augusto Lombardi, Piergiorgio Antonini and Adriano Duatti Show full author list Hide full author list

Molecules 2019, 24(1), 20; https://doi.org/10.3390/molecules24010020 - 21 Dec 2018

Cited by 34 | Viewed by 6738

Abstract

The widespread availability of novel radioactive isotopes showing nuclear characteristics suitable for diagnostic and therapeutic applications in nuclear medicine (NM) has experienced a great development in the last years, particularly as a result of key advancements of cyclotron-based radioisotope production technologies. At Legnaro [...] Read more.

The widespread availability of novel radioactive isotopes showing nuclear characteristics suitable for diagnostic and therapeutic applications in nuclear medicine (NM) has experienced a great development in the last years, particularly as a result of key advancements of cyclotron-based radioisotope production technologies. At Legnaro National Laboratories of the National Institute of Nuclear Physics (LNL-INFN), Italy, a 70-MeV high current cyclotron has been recently installed. This cyclotron will be dedicated not only to pursuing fundamental nuclear physics studies, but also to research related to other scientific fields with an emphasis on medical applications. LARAMED project was established a few years ago at LNL-INFN as a new research line aimed at exploiting the scientific power of nuclear physics for developing innovative applications to medicine. The goal of this program is to elect LNL as a worldwide recognized hub for the development of production methods of novel medical radionuclides, still unavailable for the scientific and clinical community. Although the research facility is yet to become fully operative, the LARAMED team has already started working on the cyclotron production of conventional medical radionuclides, such as Tc-99m, and on emerging radionuclides of high potential medical interest, such as Cu-67, Sc-47, and Mn-52. Full article

(This article belongs to the Special Issue New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine)

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