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Theranostic strategies involve select radionuclides that allow diagnostic imaging and tailored radionuclide therapy in the same patient. An example of a Food and Drug Administration-approved theranostic pair is the 68 Ga- and 177 Lu-labeled DOTATATE peptides, which are used to image neuroendocrine tumors, predict treatment response, and treat disease. However, when using radionuclides of 2 different elements, differences in the pharmacokinetic and pharmacodynamic profile of the agent can occur. Theranostic agents that incorporate the matched-pair radionuclides of scandium- 43 Sc/ 47 Sc or 44 Sc/ 47 Sc-would guarantee identical chemistries and pharmacologic profiles. The aim of this study was to investigate production of 43,44,47 Sc via proton-induced nuclear reactions on titanium nuclei using a 24-MeV cyclotron. Methods: Aluminum, niobium, and tantalum target holders were used with titanium foils and pressed TiO 2 to produce scandium radionuclides with proton energies of up to 24 MeV. Irradiated targets were digested using NH 4 HF 2 and HCl in a closed perfluoroalkoxy alkane vessel in 90 min. Scandium radionuclides were purified via ion-exchange chromatography using branched N,N,N',N' -tetra-2-ethylhexyldiglycolamide. The titanium target material was recovered via alkali precipitation with ammonia solution. Results: Titanium foil and TiO 2 were digested with an average efficiency of 98% ± 3% and 95% ± 1%, respectively. The typical digestion time was 45 min for titanium foil and 75 min for TiO 2 The average scandium recovery was 94% ± 3%, and the average titanium recoveries from digested titanium foil and TiO 2 after precipitation as TiO 2 were 108% ± 8% and 104% ± 5% of initial mass, respectively. Conclusion: This work demonstrated a robust method for the cyclotron production of scandium radionuclides that could be used with natural or enriched TiO 2 target material., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Scandium radioisotopes are increasingly considered viable radiolabels for targeted molecular imaging (Sc-43, Sc-44) and therapy (Sc-47). Significant technological advances have increased the quantity and quality of available radioscandium in the past decade, motivated in part by the chemical similarity of scandium to therapeutic radionuclides like Lu-177. The production and radiochemical isolation techniques applied to scandium radioisotopes are reviewed, focusing on charged particle and electron linac initiated reactions and using calcium and titanium as starting materials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: The radioisotopes of bromine are uniquely suitable radiolabels for small molecule theranostic radiopharmaceuticals but are of limited availability due to production challenges. Significantly improved methods were developed for the production and radiochemical isolation of clinical quality 76 Br, 77 Br, and 80m Br. The radiochemical quality of the radiobromine produced using these methods was tested through the synthesis of a novel 77 Br-labeled inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), a DNA damage response protein., Methods: 76 Br, 77 Br, and 80m Br were produced in high radionuclidic purity via the proton irradiation of novel isotopically-enriched Co 76 Se, Co 77 Se, and Co 80 Se intermetallic targets, respectively. Radiobromine was isolated through thermal chromatographic distillation in a vertical furnace assembly. The 77 Br-labeled PARP inhibitor was synthesized via copper-mediated aryl boronic ester radiobromination., Results: Cyclotron production yields were 103 ± 10 MBq∙μA -1 ∙h -1 for 76 Br, 88 ± 10 MBq∙μA -1 ∙h -1 for 80m Br at 16 MeV and 17 ± 1 MBq∙μA -1 ∙h -1 for 77 Br at 13 MeV. Radiobromide isolation yields were 76 ± 11% in a small volume of aqueous solution. The synthesized 77 Br-labeled PARP-1 inhibitor had a measured apparent molar activity up to 700 GBq/μmol at end of synthesis., Conclusions: A novel selenium alloy target enabled clinical-scale production of 76 Br, 77 Br, and 80m Br with high apparent molar activities, which was used to for the production of a new 77 Br-labeled inhibitor of PARP-1., Advances in Knowledge: New methods for the cyclotron production and isolation of radiobromine improved the production capacity of 77 Br by a factor of three and 76 Br by a factor of six compared with previous methods., Implications for Patient Care: Preclinical translational research of 77 Br-based Auger electron radiotherapeutics, such as those targeting PARP-1, will require the production of GBq-scale 77 Br, which necessitates next-generation, high-yielding, isotopically-enriched cyclotron targets, such as the novel intermetallic Co 77 Se., Competing Interests: Declaration of competing interest No potential conflicts of interest relevant to this article exist., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The aim of this review is to make the reader familiar with currently available radiometals, their production modes, capacities, and quality concerns related to their medical use, as well as new emerging radiometals and irradiation technologies from the perspective of their diagnostic and theranostic applications. Production methods of 177 Lu serve as an example of various issues related to the production yield, specific activity, radionuclidic and chemical purity, and production economy. Other radiometals that are currently used or explored for potential medical applications, with particular focus on their theranostic value, are discussed. Using radiometals for diagnostic imaging and therapy is on the rise. The high demand for radiometals for medical use prompts investigations towards using alternative irradiation reactions, while using existing nuclear reactors and accelerator facilities. This review discusses these production capacities and what is necessary to cover the growing demand for theranostic nuclides., (© 2019 John Wiley & Sons, Ltd.)

15 O (half-life, 122 s) is a useful radionuclide for PET applications. Current production of 15 O typically makes use of the 14 N(d,n) 15 O, 15 N(p,n) 15 O, or 16 O(p,pn) 15 O reactions using an accelerator. A novel approach for the production of 15 O is via the 16 O(γ,n) 15 O reaction using an electron linear accelerator. Photonuclear reactions using an electron linear accelerator may allow for feasible and economical production of 15 O compared with the current methods. Methods: In this work, experiments using a repurposed Clinac were conducted using oxygen-containing alumina as a target material to study the production rate of 15 O. Additional studies were conducted using a water target cell. Simulations using Geant4 were conducted to predict the activity and power dissipation in the target. Results: Bremsstrahlung radiation from the electron beam, and consequently 15 O production via photonuclear reactions, is enhanced when a high- Z material, tungsten, is placed in front of the target. The alumina irradiations provided preliminary data to optimize the beam parameters and target configuration. The optimal thickness of tungsten was 1.4 mm for both the simulated and the measured studies of alumina. Simulations of irradiated water targets showed that tungsten thicker than 1.4 mm resulted in fewer photons available to activate the water; thus, a higher current was required to achieve a fixed dose. Alternatively, for a constant tungsten thickness, more power was deposited in the target with increasing beam energy, requiring a lower current to achieve a fixed dose. Actual irradiations of a water target yielded a quantity of 15 O in the water that was consistent with expectations based on irradiations of alumina. Conclusion: Several parameters should be considered regarding the photonuclear production of 15 O for an average patient dose of 1,850 MBq (50 mCi) in 10 mL. This work illustrates a variety of machine parameters capable of achieving a reasonable patient dose. Our simulations show that the power deposited in the target for these parameters is less than that in commercially operated cyclotron targets for the production of 18 F. Thus, this work demonstrates that the photonuclear production of 15 O may be a new production path for this useful radionuclide., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: (89)Zr-labeled antibodies are being investigated in several clinical trials; however, the time requirement for synthesis of clinical doses can hinder patient throughput because of scheduling difficulties. Additionally, low specific activity due to poor labeling efficiency can require larger amounts of the radiopharmaceutical to be administered, possibly leading to adverse side effects. Here, we describe the design and evaluation of a microfluidic reactor capable of synthesizing a single clinical dose of (89)Zr-labeled antibody. (89)Zr-labeled trastuzumab was chosen for this validation because it is currently being evaluated in clinical trials for imaging human epidermal growth factor receptor 2-positive cancer patients., Methods: A microreactor fabricated from polydimethylsiloxane/glass was silanated with trimethoxy(octadecyl) silane to reduce antibody adsorption. Desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) was conjugated to trastuzumab in an 8:1 molar ratio following the literature procedures using aseptic techniques. Radiolabeling was performed by pumping (89)Zr-oxalate and DFO-Bz-trastuzumab into the microfluidic reactor at a total rate of 20 μL/min in ratios varying from 1:37 to 1:592 mg:MBq at 37°C to achieve optimal labeling., Results: Silanated reactors showed low antibody adsorption in comparison to unmodified reactors (95% monoclonal antibody recovered vs. 0% recovered). Labeling of the modified trastuzumab was shown to be achievable at a specific activity above the reported literature value of 220 MBq/mg. A high radiochemical purity was achieved without an incubation period at specific activities of less than 148 MBq/mg; however, specific activities up to 592 MBq/mg could be achieved with an incubation period. Clinical doses were able to be prepared and passed all quality control guidelines set by the Food and Drug Administration. Samples were sterile, colorless, and radiochemically pure (100%); maintained the ability to bind to the intended receptor; formed a minimal amount of aggregates (1%-4%); and were completed within 45-60 min., Conclusion: (89)Zr-labeled trastuzumab for use in a clinical setting was synthesized in a microfluidic reactor in under an hour while reducing the amount of handling required by a technician. Use of this compact platform not only could enable the use of radiolabeled antibodies to become a common practice, but also could spread the use of radiolabeled antibodies beyond locations with cyclotron facilities., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

An investigative study of the (100)Mo (p,2n)(99m)Tc reaction on a medical cyclotron using (100)Mo2C is reported. This is the first report of this compound being used as a target for this reaction. (100)Mo2C, a refractory carbide with high thermal conductivity, properties which underscore its use on a cyclotron, was synthesized using (100)MoO3. Its ease of oxidation back to (100)MoO3 under air at elevated temperatures facilitates the use of thermo-chromatography, a high temperature gas phase separation technique for the separation and isolation of (99m)Tc. Activity yields for (99m)Tc averaged 84% of the calculated theoretical yields. Additionally, the percent recovery of MoO3, the precursor for Mo2C, was consistently high at 85% ensuring a good life cycle for this target material. The produced (99m)Tc was radio-chemically pure and easily labeled MDP for imaging purposes., (© 2013.)

Specific Activity (SA), defined as the amount of radioactivity per unit mass of a compound is arguably one of the most important parameters in radiopharmaceutical development, particularly in quality control of carbon-11 and fluorine-18 labeled compounds. This review article will outline the progression of improvements in SA over the last few decades. The International Symposium of Radiopharmaceutical Chemistry (ISRC/ISRS) abstracts were an excellent source of materials for this review and will be referenced throughout., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer. [ABSTRACT FROM AUTHOR]

Molecular imaging is an important part of modern medicine which enables the non-invasive identification and characterization of diseases. With the advancement of radiochemistry and scanner technology, nuclear medicine is providing insight into efficient treatment options for individual patients. Titanium-45 (45Ti) is a lesser-explored radionuclide that is garnering increasing interest for the development of positron emission tomography (PET) radiopharmaceuticals. This review discusses aspects of this radionuclide including production, purification, radiochemistry development, and molecular imaging studies. [ABSTRACT FROM AUTHOR]

Despite its prevalence in the environment, the chemistry of the Ti4+ ion has long been relegated to organic solutions or hydrolyzed TiO2 polymorphs. A knowledge gap in stabilizing molecular Ti4+ species in aqueous environments has prevented the use of this ion for various applications such as radioimaging, design of water‐compatible metal–organic frameworks (MOFs), and aqueous‐phase catalysis applications. Herein, we show a thorough thermodynamic screening of bidentate chelators with Ti4+ in aqueous solution, as well as computational and structural analyses of key compounds. In addition, the hexadentate analogues of catechol (benzene‐1,2‐diol) and deferiprone (3‐hydroxy‐1,2‐dimethyl‐4(1H)‐pyridone), TREN‐CAM and THPMe respectively, were assessed for chelation of the 45Ti isotope (t1/2=3.08 h, β+=85 %, Eβ+=439 keV) towards positron emission tomography (PET) imaging applications. Both were found to have excellent capacity for kit‐formulation, and [45Ti]Ti‐TREN‐CAM was found to have remarkable stability in vivo. [ABSTRACT FROM AUTHOR]

The emerging success of [68Ga/177Lu]Ga/Lu-DOTATATE as a theranostic pair has spurred interest in other isotopes as potential theranostic combinations. Here, we review cobalt-55 and cobalt-58m as a potential theranostic pair. Radionuclidically pure cobalt-55 and cobalt-58m have been produced on small cyclotrons with high molar activity. In vitro, DOTATOC labeled with cobalt has shown greater affinity for SSTR2 than DOTATOC labeled with gallium and yttrium. Similarly, [58mCo]Co-DOTATATE has shown improved cell-killing capabilities as compared to DOTATATE labeled with either indium-111 or lutetium-177. Finally, PET imaging with an isotope such as cobalt-55 allows for image acquisition at much later timepoints than gallium, allowing for an increased degree of biological clearance of non-bound radiotracer. We discuss the accelerator targetry and radiochemistry used to produce cobalt-55,58m, emphasizing the implications of these techniques to downstream radiotracers being developed for imaging and therapy. [ABSTRACT FROM AUTHOR]

There is a growing need for the production of radioisotopes for both diagnostic and therapeutic medical applications. Radioisotopes that are produced using the (n,γ) or (γ,n) reactions, however, typically result in samples with low specific activity (radioactivity/gram) due to the high abundance of target material of the same element. One method to effectively remove the isotopic impurity is electro-magnetic mass separation. An Ion Source Test Facility has been constructed at TRIUMF to develop high-intensity, high-efficiency, reliable ion sources for purification of radioactive isotopes, particularly those used in nuclear medicine. In progress studies are presented. [ABSTRACT FROM AUTHOR]

Chelators play a crucial role in the development of metal-based radiopharmaceuticals, and with the continued interest in 68Ga and increasing availability of new radiometals such as 43Sc/47Sc and 45Ti, there is a growing demand for tailored chelators that can form stable complexes with these metals. This work reports the synthesis and characterization of a hexadentate tris-1,2-hydroxypyridonone chelator HOPO-O 6 -C4 and its in vitro and in vivo evaluation with the above mentioned radiometals. To investigate the affinity of HOPO-O 6 -C4, macroscopic studies were performed with Sc3+, and Ga3+ followed by DFT structural optimization of the Sc3+, Ga3+ and Ti4+ complexes. Further tracer studies with 43Sc (and 47Sc), 45Ti, and 68Ga were performed to determine the potential for positron emission tomography (PET) imaging with these complexes. In vitro stability studies followed by in vivo imaging and biodistribution studies were performed to understand the kinetic stability of the resultant radiometal-complexes of HOPO-O 6 -C4. Promising radiolabeling results with HOPO-O 6 -C4 were obtained with 43Sc, 47Sc, 45Ti, and 68Ga radionuclides; rapid radiolabeling was observed at 37 °C and pH 7 in under 30-min. Apparent molar activity measurements were performed for radiolabeling of HOPO-O 6 -C4 with 43Sc (4.9 ± 0.26 GBq/μmol), 47Sc (1.58 ± 0.01 GBq/μmol), 45Ti (11.5 ± 1.6 GBq/μmol) and 68Ga (5.74 ± 0.7 GBq/μmol), respectively. Preclinical in vivo imaging studies resulted in promising results with [68Ga]Ga-HOPO-O 6 -C4 indicating a rapid clearance through hepatic excretion route and no decomplexation whereas [43Sc]Sc-HOPO-O 6 -C4, [47Sc]Sc-HOPO-O 6 -C4 and [45Ti]Ti-HOPO-O 6 -C4 showed modest and significant evidence of decomplexation, respectively. The tris-1,2-HOPO chelator HOPO-O 6 -C4 is a promising scaffold for elaboration into a 68Ga- based radiopharmaceutical. [Display omitted] [ABSTRACT FROM AUTHOR]

This work focused on the production and purification of the positron emitter 52Mn (t 1/2 = 5.6 d) via the natCr(p,n)52Mn reaction, using a TR24 cyclotron and a semi-automated system for the purification of 52Mn. Based on two-column and three-column systems, the recovery of 52Mn was 79.7 ± 6.2% (n = 3) and 70.8 ± 3.3% (n = 3), with processing times of 6.9 ± 0.5 h and 8.2 ± 0.6 h, respectively. • 52Mn was produced via irradiation of Cr foils using a solid-target coin system. • A semi-automated module was designed, constructed and optimized for the purification of 52Mn. • ICP-MS was used for elemental analysis of the starting material, after each column and waste for purifications of 52Mn. • HPGe was utilized for the irradiated samples to verify a high purity product with 54Mn contaminants <0.25%. [ABSTRACT FROM AUTHOR]

Titanium-45 (t 1/2 = 3.08 h) is a radiometal with excellent nuclear characteristics, including a high positron branching ratio (85%) and low average positron energy (0.439 MeV), for the development of PET imaging agents. 45Ti was produced via the 45Sc(p,n)45Ti reaction on the University of Alabama at Birmingham TR24 cyclotron in GBq quantities. Optimized separation methods were developed and preliminary radiochemistry studies were also carried out. This work shows 45Ti is a promising radiometal for future studies. • 45Ti was produced via irradiation of Sc foil using a solid-target coin system. • Radionuclidically pure product at yields suitable for research were obtained. • An optimized separation method for the use of 45Ti was developed. • Complexation studies of 45Ti with deferoxamine were conducted. [ABSTRACT FROM AUTHOR]