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New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 79948

Special Issue Editors


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Guest Editor
Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
Interests: radiopharmaceuticals science and technology; preclinical evaluation and translation into clinical application; nuclear medicine; molecular imaging

E-Mail Website
Guest Editor
Department of Chemical, Pharmaceutical and Agricultural Sciences (DoCPAS), University of Ferrara, 44121 Ferrara, Italy
Interests: inorganic chemistry; radiopharmaceuticals; nuclear imaging; radiochemistry; radiometals production
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
1. Legnaro National Laboratories of the National Institute of Nuclear Physics (INFN-LNL), Viale dell'Università, 2, 35020 Legnaro (PD), Italy
2. Dpt. of Morphology, Surgical and Experimental Medicine, University of Ferrara, Via L. Borsari, 46, 44121 Ferrara, Italy
Interests: radioisotopes cyclotron-production; nuclear medicine; radiometals separation; synthesis module automation; radiopharmaceuticals
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nuclear Medicine is one of the most important imaging modalities and therapeutic approaches for the treatment of many critical diseases. The success of nuclear medicine in clinics has been intimately linked to the availability of new radionuclides and the discovery of new radiopharmaceuticals. The field of radiopharmaceuticals is constantly evolving thanks to the great contribution of specialists coming from different disciplines, such as radiochemistry, inorganic and organic chemistry, biochemistry, pharmacology, nuclear medicine, physics, etc. In particular, the use of radiometals has experienced a great increase as a result of the development of radionuclides production technologies. Their employment in all Nuclear Medicine branch (SPECT/PET diagnostic, therapy and theranostics) is regulated by their physical characteristics, such as half-life, radiation emission energy and type (γ, β+, β-, auger, α), availability and chemical ability to coordinate with ligands.

The actual trend in the nuclear medicine research field is the use of radiometals for PET and SPECT, such as 68Ga, 64Cu, 89Zr, 44Sc, 86Y, 52Mn, 99mTc, etc., for therapy, such as 177Lu, 90Y ,89Sr, 223Ra, 225Ac, etc., and for theranostics, such as 67Cu, 47Sc, theranostics pairs, etc.

You are cordially invited to contribute to this Special Issue “New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine” with original articles, as well as reviews and short communications. Areas of interest include, but are not limited to:

  • Radiometals production: methods and technology
  • Radiometals separation: methods and technology
  • Radiopharmaceuticals synthesis automation: methods and technology
  • Theranostics radiopharmaceuticals
  • Multimodality imaging radiopharmaceuticals
  • Innovative radio-probes for nuclear imaging or therapy
  • Individualized Dosimetry for Theranostics

For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on the website.

Dr. Licia Uccelli
Dr. Alessandra Boschi
Dr. Petra Martini
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Nuclear Medicine
  • PET and SPECT radiopharmaceuticals
  • Theranostics tracers
  • Radionuclides therapy
  • Radionuclides imaging
  • Multimodality approaches
  • Dosimetry
  • Personalized medicine
  • Automation technology
  • Production technology
  • Separation technology
  • Labelling techniques

Published Papers (16 papers)

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14 pages, 926 KiB  
Article
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 6 | Viewed by 4167
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
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24 pages, 5413 KiB  
Article
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 18 | Viewed by 4978
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
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10 pages, 1535 KiB  
Article
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 10 | Viewed by 4452
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
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11 pages, 1235 KiB  
Article
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 2630
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
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19 pages, 2321 KiB  
Article
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 9 | Viewed by 3568
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
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14 pages, 2403 KiB  
Article
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 3965 | 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
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13 pages, 2297 KiB  
Article
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 31 | Viewed by 4341
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
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22 pages, 6529 KiB  
Article
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 5781
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
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13 pages, 2477 KiB  
Article
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 22 | Viewed by 5258
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 (13) 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 (13) 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
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15 pages, 2023 KiB  
Article
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 15 | Viewed by 3984
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
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13 pages, 1666 KiB  
Article
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 9 | Viewed by 3249
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 (t1/2 = 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 (t1/2 = 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
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12 pages, 8133 KiB  
Article
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 4421
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
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19 pages, 6498 KiB  
Article
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 6534
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
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Review

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29 pages, 1765 KiB  
Review
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 37 | Viewed by 8757
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
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17 pages, 3798 KiB  
Review
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 20 | Viewed by 5712
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
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Other

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14 pages, 10722 KiB  
Letter
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 Duattiadd Show full author list remove Hide full author list
Molecules 2019, 24(1), 20; https://doi.org/10.3390/molecules24010020 - 21 Dec 2018
Cited by 33 | Viewed by 6103
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
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