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

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 39178

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Special Issue Editors

Dr. Alessandra Boschi

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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

Dr. Petra Martini

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Guest Editor

Department of Environmental and Prevention Sciences (DEPS), University of Ferrara Via Luigi Borsari, 46 44121 Ferrara, Italy
Interests: radioisotope cyclotron production; radiometal separation; synthesis module automation; radiopharmaceuticals; radiochemistry; nuclear medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Following the great success of the previous Molecules Special Issue entitled "New Trends in Production and Applications of Metal Radionuclides for Nuclear Medicine", which collected 16 papers of high scientific value, we are pleased to present you this new opportunity to share your scientific experience on “Metal-Based Radiopharmaceuticals in Inorganic Chemistry”.

The field of radiopharmaceuticals is constantly evolving thanks to the great contribution of specialists coming from different disciplines such as inorganic chemistry, radiochemistry, organic and 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. In this particular area, inorganic chemistry skills are mainly involved in developing target-specific radiopharmaceuticals based on radiometals for non-invasive disease detection and cancer radiotherapy.

The production and applications of conventional and newly emerging research radiometals for diagnosis, therapy, and theranostics are the main focus of this new Special Issue “Metal-Based Radiopharmaceuticals in Inorganic Chemistry” for which you are cordially invited to contribute with original articles, as well as reviews and short communications. Areas of interest include, but are not limited to the following:

Chemistry of radiometals
Radiometals production: methods and technology
Radiometals separation: methods and technology
Radiopharmaceuticals chemistry
Radiopharmaceuticals synthesis automation: methods and technology
Theranostics radiopharmaceuticals
Multimodality imaging radiopharmaceuticals
Innovative radio-probes for nuclear imaging or therapy
Individualized dosimetry for theranostics

Dr. Alessandra Boschi
Dr. Petra Martini
Guest Editors

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Keywords

Radiometals inorganic chemistry
Coordination chemistry
PET and SPECT radiopharmaceuticals
Theranostics radiopharmaceuticals
Radionuclide therapy
Auger-electron radionuclide therapy
Multimodality approaches
Dosimetry
Personalized medicine
Automation technology
Production technology
Labeling techniques

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Published Papers (13 papers)

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Editorial

Jump to: Research, Review

6 pages, 215 KiB

Open AccessEditorial

Metal-Based Radiopharmaceuticals in Inorganic Chemistry

by Alessandra Boschi and Petra Martini

Molecules 2023, 28(5), 2290; https://doi.org/10.3390/molecules28052290 - 1 Mar 2023

Viewed by 1768

Abstract

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

Research

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15 pages, 2043 KiB

Open AccessArticle

²²⁵Ac-rHDL Nanoparticles: A Potential Agent for Targeted Alpha-Particle Therapy of Tumors Overexpressing SR-BI Proteins

by Tania Hernández-Jiménez, Guillermina Ferro-Flores, Enrique Morales-Ávila, Keila Isaac-Olivé, Blanca Ocampo-García, Liliana Aranda-Lara, Clara Santos-Cuevas, Myrna Luna-Gutiérrez, Laura De Nardo, Antonio Rosato and Laura Meléndez-Alafort

Molecules 2022, 27(7), 2156; https://doi.org/10.3390/molecules27072156 - 27 Mar 2022

Cited by 9 | Viewed by 2612

Abstract

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. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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11 pages, 2144 KiB

Open AccessArticle

Yields of Photo-Proton Reactions on Nuclei of Nickel and Separation of Cobalt Isotopes from Irradiated Targets

by Andrey G. Kazakov, Julia S. Babenya, Taisya Y. Ekatova, Sergey S. Belyshev, Vadim V. Khankin, Alexander A. Kuznetsov, Sergey E. Vinokurov and Boris F. Myasoedov

Molecules 2022, 27(5), 1524; https://doi.org/10.3390/molecules27051524 - 24 Feb 2022

Cited by 1 | Viewed by 2094

Abstract

Nowadays, cobalt isotopes ⁵⁵Co, ⁵⁷Co, and ^58mCo are considered to be promising radionuclides in nuclear medicine, with ⁵⁵Co receiving the most attention as an isotope for diagnostics by positron emission tomography. One of the current research directions is dedicated to its production using electron accelerators (via photonuclear method). In our work, the yields of nuclear reactions occurring during the irradiation of ^natNi and ⁶⁰Ni by bremsstrahlung photons with energy up to 55 MeV were determined. A method of fast and simple cobalt isotopes separation from irradiated targets using extraction chromatography was developed. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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22 pages, 7375 KiB

Open AccessArticle

Synthesis of Ionizable Calix[4]arenes for Chelation of Selected Divalent Cations

by Markus Blumberg, Karrar Al-Ameed, Erik Eiselt, Sandra Luber and Constantin Mamat

Molecules 2022, 27(5), 1478; https://doi.org/10.3390/molecules27051478 - 22 Feb 2022

Cited by 4 | Viewed by 2931

Abstract

Two sets of functionalised calix[4]arenes, either with a 1,3-crown ether bridge or with an open-chain oligo ether moiety in 1,3-position were prepared and further equipped with additional deprotonisable sulfonamide groups to establish chelating systems for selected cations Sr²⁺, Ba²⁺, and Pb²⁺ ions. To improve the complexation behaviour towards these cations, calix[4]arenes with oligo ether groups and modified crowns of different sizes were synthesized. Association constants were determined by UV/Vis titration in acetonitrile using the respective perchlorate salts and logK values between 3.2 and 8.0 were obtained. These findings were supported by the calculation of the binding energies exemplarily for selected complexes with Ba²⁺. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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15 pages, 1354 KiB

Open AccessArticle

A High Separation Factor for ¹⁶⁵Er from Ho for Targeted Radionuclide Therapy

by Isidro Da Silva, Taylor R. Johnson, Jason C. Mixdorf, Eduardo Aluicio-Sarduy, Todd E. Barnhart, R. Jerome Nickles, Jonathan W. Engle and Paul A. Ellison

Molecules 2021, 26(24), 7513; https://doi.org/10.3390/molecules26247513 - 11 Dec 2021

Cited by 7 | Viewed by 3142

Abstract

Background: Radionuclides emitting Auger electrons (AEs) with low (0.02–50 keV) energy, short (0.0007–40 µm) range, and high (1–10 keV/µm) linear energy transfer may have an important role in the targeted radionuclide therapy of metastatic and disseminated disease. Erbium-165 is a pure AE-emitting radionuclide that is chemically matched to clinical therapeutic radionuclide ¹⁷⁷Lu, making it a useful tool for fundamental studies on the biological effects of AEs. This work develops new biomedical cyclotron irradiation and radiochemical isolation methods to produce ¹⁶⁵Er suitable for targeted radionuclide therapeutic studies and characterizes a new such agent targeting prostate-specific membrane antigen. Methods: Biomedical cyclotrons proton-irradiated spot-welded Ho_(m) targets to produce ¹⁶⁵Er, which was isolated via cation exchange chromatography (AG 50W-X8, 200–400 mesh, 20 mL) using alpha-hydroxyisobutyrate (70 mM, pH 4.7) followed by LN2 (20–50 µm, 1.3 mL) and bDGA (50–100 µm, 0.2 mL) extraction chromatography. The purified ¹⁶⁵Er was radiolabeled with standard radiometal chelators and used to produce and characterize a new AE-emitting radiopharmaceutical, [¹⁶⁵Er]PSMA-617. Results: Irradiation of 80–180 mg ^natHo targets with 40 µA of 11–12.5 MeV protons produced ¹⁶⁵Er at 20–30 MBq·µA⁻¹·h⁻¹. The 4.9 ± 0.7 h radiochemical isolation yielded ¹⁶⁵Er in 0.01 M HCl (400 µL) with decay-corrected (DC) yield of 64 ± 2% and a Ho/¹⁶⁵Er separation factor of (2.8 ± 1.1) · 10⁵. Radiolabeling experiments synthesized [¹⁶⁵Er]PSMA-617 at DC molar activities of 37–130 GBq·µmol⁻¹. Conclusions: A 2 h biomedical cyclotron irradiation and 5 h radiochemical separation produced GBq-scale ¹⁶⁵Er suitable for producing radiopharmaceuticals at molar activities satisfactory for investigations of targeted radionuclide therapeutics. This will enable fundamental radiation biology experiments of pure AE-emitting therapeutic radiopharmaceuticals such as [¹⁶⁵Er]PSMA-617, which will be used to understand the impact of AEs in PSMA-targeted radionuclide therapy of prostate cancer. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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12 pages, 4453 KiB

Open AccessArticle

A Universal Cassette-Based System for the Dissolution of Solid Targets

by Gabriele Sciacca, Petra Martini, Sara Cisternino, Liliana Mou, Jonathan Amico, Juan Esposito, Giancarlo Gorgoni and Emiliano Cazzola

Molecules 2021, 26(20), 6255; https://doi.org/10.3390/molecules26206255 - 16 Oct 2021

Cited by 12 | Viewed by 2557

Abstract

Cyclotron-based radionuclides production by using solid targets has become important in the last years due to the growing demand of radiometals, e.g., ⁶⁸Ga, ⁸⁹Zr, ^43/47Sc, and ^52/54Mn. This shifted the focus on solid target management, where the first fundamental step of the radiochemical processing is the target dissolution. Currently, this step is generally performed with commercial or home-made modules separated from the following purification/radiolabelling modules. The aim of this work is the realization of a flexible solid target dissolution system to be easily installed on commercial cassette-based synthesis modules. This would offer a complete target processing and radiopharmaceutical synthesis performable in a single module continuously. The presented solid target dissolution system concept relies on an open-bottomed vial positioned upon a target coin. In particular, the idea is to use the movement mechanism of a syringe pump to position the vial up and down on the target, and to exploit the heater/cooler reactor of the module as a target holder. All the steps can be remotely controlled and are incorporated in the cassette manifold together with the purification and radiolabelling steps. The performance of the device was tested by processing three different irradiated targets under different dissolution conditions. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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9 pages, 9695 KiB

Open AccessArticle

Highly Efficient Micro-Scale Liquid-Liquid In-Flow Extraction of ^99mTc from Molybdenum

by Petra Martini, Licia Uccelli, Adriano Duatti, Lorenza Marvelli, Juan Esposito and Alessandra Boschi

Molecules 2021, 26(18), 5699; https://doi.org/10.3390/molecules26185699 - 21 Sep 2021

Cited by 10 | Viewed by 3382

Abstract

The trend to achieve even more compact-sized systems is leading to the development of micro-scale reactors (lab-on-chip) in the field of radiochemical separation and radiopharmaceutical production. Technetium-99m extraction from both high and low specific activity molybdenum could be simply performed by MEK-driven solvent extraction if it were not for unpractical automation. The aim of this work is to develop a solvent extraction and separation process of technetium from molybdenum in a micro-scale in-flow chemistry regime with the aid of a capillary loop and a membrane-based separator, respectively. The developed system is able to extract and separate quantitatively and selectively (91.0 ± 1.8% decay corrected) the [^99mTc]TcO₄Na in about 20 min, by using a ZAIPUT separator device. In conclusion, we demonstrated for the first time in our knowledge the high efficiency of a MEK-based solvent extraction process of ^99mTc from a molybdenum-based liquid phased in an in-flow micro-scale regime. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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11 pages, 2494 KiB

Open AccessArticle

Chemical Conversion of Hardly Ionizable Rhenium Aryl Chlorocomplexes with p-Substituted Anilines

by Martin Štícha, Ivan Jelínek and Mikuláš Vlk

Molecules 2021, 26(11), 3427; https://doi.org/10.3390/molecules26113427 - 5 Jun 2021

Cited by 1 | Viewed by 2230

Abstract

Fast and selective analytical methods help to ensure the chemical identity and desired purity of the prepared complexes before their medical application, and play an indispensable role in clinical practice. Mass spectrometry, despite some limitations, is an integral part of these methods. In the context of mass spectrometry, specific problems arise with the low ionization efficiency of particular analytes. Chemical derivatization was used as one of the most effective methods to improve the analyte’s response and separation characteristics. The Schotten–Baumann reaction was successfully adapted for the derivatization of ESI hardly ionizable Re(VII) bis(catechol) oxochlorocomplex. Various alkyl and halogen p-substituted anilines as possible derivatization agents were tested. Unlike the starting complex, the reaction products were easily ionizable in electrospray, providing structurally characteristic molecular and fragment anions. DFT computer modeling, which proposed significant conformation changes of prepared complexes within their deprotonation, proved to have a close link to MS spectra. High-resolution MS and MS/MS measurements complemented with collision-induced dissociation experiments for detailed specification of prepared complexes’ fragmentation pathways were used. The specified fragmentation schemes were analogous for all studied derivatives, with an exception for [Re(O)(Cat)₂PIPA]. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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23 pages, 4495 KiB

Open AccessArticle

Preliminary Study of a 1,5-Benzodiazepine-Derivative Labelled with Indium-111 for CCK-2 Receptor Targeting

by Marco Verona, Sara Rubagotti, Stefania Croci, Sophia Sarpaki, Francesca Borgna, Marianna Tosato, Elisa Vettorato, Giovanni Marzaro, Francesca Mastrotto and Mattia Asti

Molecules 2021, 26(4), 918; https://doi.org/10.3390/molecules26040918 - 9 Feb 2021

Cited by 13 | Viewed by 3731

Abstract

The cholecystokinin-2 receptor (CCK-2R) is overexpressed in several human cancers but displays limited expression in normal tissues. For this reason, it is a suitable target for developing specific radiotracers. In this study, a nastorazepide-based ligand functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator (IP-001) was synthesized and labelled with indium-111. The radiolabeling process yielded >95% with a molar activity of 10 MBq/nmol and a radiochemical purity of >98%. Stability studies have shown a remarkable resistance to degradation (>93%) within 120 h of incubation in human blood. The in vitro uptake of [¹¹¹In]In-IP-001 was assessed for up to 24 h on a high CCK-2R-expressing tumor cell line (A549) showing maximal accumulation after 4 h of incubation. Biodistribution and single photon emission tomography (SPECT)/CT imaging were evaluated on BALB/c nude mice bearing A549 xenograft tumors. Implanted tumors could be clearly visualized after only 4 h post injection (2.36 ± 0.26% ID/cc), although a high amount of radiotracer was also found in the liver, kidneys, and spleen (8.25 ± 2.21%, 6.99 ± 0.97%, and 3.88 ± 0.36% ID/cc, respectively). Clearance was slow by both hepatobiliary and renal excretion. Tumor retention persisted for up to 24 h, with the tumor to organs ratio increasing over-time and ending with a tumor uptake (1.52 ± 0.71% ID/cc) comparable to liver and kidneys. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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10 pages, 5968 KiB

Open AccessArticle

Safety Evaluation of an Alpha-Emitter Bismuth-213 Labeled Antibody to (1→3)-β-Glucan in Healthy Dogs as a Prelude for a Trial in Companion Dogs with Invasive Fungal Infections

by Muath Helal, Kevin J. H. Allen, Hilary Burgess, Rubin Jiao, Mackenzie E. Malo, Matthew Hutcheson, Ekaterina Dadachova and Elisabeth Snead

Molecules 2020, 25(16), 3604; https://doi.org/10.3390/molecules25163604 - 8 Aug 2020

Cited by 7 | Viewed by 2603

Abstract

Background: With the limited options available for therapy to treat invasive fungal infections (IFI), radioimmunotherapy (RIT) can potentially offer an effective alternative treatment. Microorganism-specific monoclonal antibodies have shown promising results in the experimental treatment of fungal, bacterial, and viral infections, including our recent and encouraging results from treating mice infected with Blastomyces dermatitidis with ²¹³Bi-labeled antibody 400-2 to (1→3)-β-glucan. In this work, we performed a safety study of ²¹³Bi-400-2 antibody in healthy dogs as a prelude for a clinical trial in companion dogs with acquired invasive fungal infections and later on in human patients with IFI. Methods: Three female beagle dogs (≈6.1 kg body weight) were treated intravenously with 155.3, 142.5, or 133.2 MBq of ²¹³Bi-400-2 given as three subfractions over an 8 h period. RBC, WBC, platelet, and blood serum biochemistry parameters were measured periodically for 6 months post injection. Results: No significant acute or long-term side effects were observed after RIT injections; only a few parameters were mildly and transiently outside reference change value limits, and a transient atypical morphology was observed in the circulating lymphocyte population of two dogs. Conclusions: These results demonstrate the safety of systemic ²¹³Bi-400-2 administration in dogs and provide encouragement to pursue evaluation of RIT of IFI in companion dogs. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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11 pages, 1292 KiB

Open AccessArticle

Production and Semi-Automated Processing of ⁸⁹Zr Using a Commercially Available TRASIS MiniAiO Module

by Vijay Gaja, Jacqueline Cawthray, Clarence R. Geyer and Humphrey Fonge

Molecules 2020, 25(11), 2626; https://doi.org/10.3390/molecules25112626 - 5 Jun 2020

Cited by 11 | Viewed by 3399

Abstract

The increased interest in ⁸⁹Zr-labelled immunoPET imaging probes for use in preclinical and clinical studies has led to a rising demand for the isotope. The highly penetrating 511 and 909 keV photons emitted by ⁸⁹Zr deliver an undesirably high radiation dose, which makes it difficult to produce large amounts manually. Additionally, there is a growing demand for Good Manufacturing Practices (GMP)-grade radionuclides for clinical applications. In this study, we have adopted the commercially available TRASIS mini AllinOne (miniAiO) automated synthesis unit to achieve efficient and reproducible batches of ⁸⁹Zr. This automated module is used for the target dissolution and separation of ⁸⁹Zr from the yttrium target material. The ⁸⁹Zr is eluted with a very small volume of oxalic acid (1.5 mL) directly over the sterile filter into the final vial. Using this sophisticated automated purification method, we obtained satisfactory amount of ⁸⁹Zr in high radionuclidic and radiochemical purities in excess of 99.99%. The specific activity of three production batches were calculated and was found to be in the range of 1351–2323 MBq/µmol. ICP-MS analysis of final solutions showed impurity levels always below 1 ppm. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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14 pages, 2463 KiB

Open AccessArticle

Hybrid Imaging Agents for Pretargeting Applications Based on Fusarinine C—Proof of Concept

by Dominik Summer, Milos Petrik, Sonja Mayr, Martin Hermann, Piriya Kaeopookum, Joachim Pfister, Maximilian Klingler, Christine Rangger, Hubertus Haas and Clemens Decristoforo

Molecules 2020, 25(9), 2123; https://doi.org/10.3390/molecules25092123 - 1 May 2020

Cited by 9 | Viewed by 3145

Abstract

Hybrid imaging combining the beneficial properties of radioactivity and optical imaging within one imaging probe has gained increasing interest in radiopharmaceutical research. In this study, we modified the macrocyclic gallium-68 chelator fusarinine C (FSC) by conjugating a fluorescent moiety and tetrazine (Tz) moieties. The resulting hybrid imaging agents were used for pretargeting applications utilizing click reactions with a trans-cyclooctene (TCO) tagged targeting vector for a proof of principle both in vitro and in vivo. Starting from FSC, the fluorophores Sulfocyanine-5, Sulfocyanine-7, or IRDye800CW were conjugated, followed by introduction of one or two Tz motifs, resulting in mono and dimeric Tz conjugates. Evaluation included fluorescence microscopy, binding studies, logD, protein binding, in vivo biodistribution, µPET (micro-positron emission tomography), and optical imaging (OI) studies. ⁶⁸Ga-labeled conjugates showed suitable hydrophilicity, high stability, and specific targeting properties towards Rituximab-TCO pre-treated CD20 expressing Raji cells. Biodistribution studies showed fast clearance and low accumulation in non-targeted organs for both SulfoCy5- and IRDye800CW-conjugates. In an alendronate-TCO based bone targeting model the dimeric IRDye800CW-conjugate resulted in specific targeting using PET and OI, superior to the monomer. This proof of concept study showed that the preparation of FSC-Tz hybrid imaging agents for pretargeting applications is feasible, making such compounds suitable for hybrid imaging applications. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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Review

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18 pages, 523 KiB

Open AccessReview

⁶⁷Cu Production Capabilities: A Mini Review

by Liliana Mou, Petra Martini, Gaia Pupillo, Izabela Cieszykowska, Cathy S. Cutler and Renata Mikołajczak

Molecules 2022, 27(5), 1501; https://doi.org/10.3390/molecules27051501 - 23 Feb 2022

Cited by 34 | Viewed by 4048

Abstract

Is the ⁶⁷Cu production worldwide feasible for expanding preclinical and clinical studies? How can we face the ingrowing demands of this emerging and promising theranostic radionuclide for personalized therapies? This review looks at the different production routes, including the accelerator- and reactor-based ones, providing a comprehensive overview of the actual ⁶⁷Cu supply, with brief insight into its use in non-clinical and clinical studies. In addition to the most often explored nuclear reactions, this work focuses on the ⁶⁷Cu separation and purification techniques, as well as the target material recovery procedures that are mandatory for the economic sustainability of the production cycle. The quality aspects, such as radiochemical, chemical, and radionuclidic purity, with particular attention to the coproduction of the counterpart ⁶⁴Cu, are also taken into account, with detailed comparisons among the different production routes. Future possibilities related to new infrastructures are included in this work, as well as new developments on the radiopharmaceuticals aspects. Full article

(This article belongs to the Special Issue Metal-Based Radiopharmaceuticals in Inorganic Chemistry)

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