Current Radiopharmaceuticals - Volume 14, Issue 4, 2021

Despite interesting properties, the use of ⁶⁷Cu, ¹⁸⁶Re and ⁴⁷Sc theranostic radionuclides in preclinical studies and clinical trials is curtailed by their limited availability due to a lack of widely established production methods. An IAEA Coordinated Research Project (CRP) was initiated to identify important technical issues related to the production and quality control of these emerging radionuclides and related radiopharmaceuticals, based on the request from IAEA Member States. The international team worked on targetry, separation, quality control and radiopharmaceutical aspects of the radionuclides obtained from research reactors and cyclotrons leading to preparation of a standard recommendations for all Member States. The CRP was initiated in 2016 with fourteen participants from thirteen Member States from four continents. Extraordinary results on the production, quality control and preclinical evaluation of selected radionuclides were reported in this project that was finalized in 2020. The outcomes, outputs and results of this project achieved by participating Member States are described in this minireview.

Gallium-68 is a positron-emitting nuclide that has recently achieved clinical acceptance as the diagnostic radionuclide in PET tracers used for theranostic studies of lutetium-177 labeled therapeutic drugs due to the ease of access provided by germanium-68/gallium-68 generators. An alternative method of production currently being explored uses accelerators to form gallium-68 directly. This review of gallium-68 production strategies discusses available accelerator targetry at a range of beam energies and intensities, the many radiochemical separation techniques available to isolate Ga-68 from irradiated targets, isotopically enriched target material recovery, and the implications of these techniques for downstream radiolabeling applications.

The present review describes the methodological aspects and prospects of the production of Positron Emission Tomography (PET) radiometals in a liquid target using low-medium energy medical cyclotrons. The main objective of this review is to delineate and discuss the critical factors involved in the liquid target production of radiometals, including type of salt solution, solution composition, beam energy, beam current, the effect of irradiation duration (length of irradiation) and challenges posed by in-target chemistry in relation with irradiation parameters. We also summarize the optimal parameters for the production of various radiometals in liquid targets. Additionally, we discuss the future prospects of PET radiometals production in the liquid targets for academic research and clinical applications. Significant emphasis has been given to the production of ⁶⁸Ga using liquid targets due to the growing demand for ⁶⁸Ga labeled PSMA vectors, [⁶⁸Ga]- Ga-DOTATATE, [⁶⁸Ga]Ga-DOTANOC and some upcoming ⁶⁸Ga labeled radiopharmaceuticals. Other PET radiometals included in the discussion are ⁸⁶Y, ⁶³Zn and ⁸⁹Zr.

Over the last several years there has been a growing interest in the use of radiopharmaceuticals labeled with metallic radionuclides, especially isotopes of copper (Cu). Cu has a unique set of radionuclides with a potential application not only for diagnostic imaging but also for applications in targeted radionuclide therapy. To review the methods and routes used for the production of Cu radionuclides in compact medical cyclotrons (Ep<20 MeV) using solid targets. The cyclotron production of Cu radionuclides using solid targets has proven to be very efficient. The large number of compact medical cyclotrons distributed worldwide, and the high target yields in the production of Cu radionuclides achieved at these energies, form a potential network of distribution to satisfy the growing demand for these radionuclides, especially ⁶⁴Cu.

The successful use of theranostic twins in neuroendocrine tumors (NET) is the pioneering approach to radionuclide therapy in other tumor types. ⁶⁴Cu/¹⁸F PSMA for molecular imaging with PET-CT and peptide radioligand therapy (PRLT) with 177Lu labeled PSMA inhibitors are the next theranostic twins in nuclear medicine. ⁶⁸Ga/ ⁶⁴Cu/¹⁸F PSMA PET-CT detects metastatic prostate cancer with high diagnostic sensitivity and specificity and can be used to select patients for PRLT and evaluate therapy response. Radionuclide therapy with ¹⁷⁷Lu-PSMA inhibitors has been shown to be effective in the treatment of metastatic CRPC.

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.

The tumor microenvironment is a dynamic ecosystem where malignant cells interact with the stromal cells sustaining and promoting tumor growth and metastasis. Cancer-associated fibroblasts (CAFs) are the major component of tumor stroma. CAFs control key tumorigenic activities by participating in immune evasion and suppression, extracellular matrix remodeling, neo-angiogenesis, and drug resistance. Therefore, targeting CAFs emerges as an attractive anti-cancer strategy. This review summarized recent advancements in targeting CAFs with diagnostic and therapeutic radiopharmaceuticals using clinically-promising biomarkers. The efforts to improve clinical outcomes via the application of new radiotheranostic compounds are discussed in the context of radionuclide, the pharmacophore, and, more generally, in terms of biomarker specificity and expression across different cancers and CAF phenotypes.

Targeted Radionuclide Therapies (TRTs) based on Auger emitting radionuclides have the potential to deliver extremely selective therapeutic payloads on the cellular level. However, to fully exploit this potential, suitable radionuclides need to be applied in combination with appropriate delivery systems. In this review, we summarize the state-of-the-art production, purification, chelation and applications of two promising candidates for Targeted Auger Therapy, namely antimony- 119 (¹¹⁹Sb) and mercury-197 (¹⁹⁷Hg). Both radionuclides have great potential to become efficient tools for TRT. We also highlight our current progress on the production of both radionuclides at TRIUMF and the University of Wisconsin.

Background: Expanding the range of metal-based PET radiopharmaceuticals that can be produced by the widely available network of biomedical cyclotrons is a major priority. Copper- 61 is a positron emitter with very favourable physical (61.5% β+, 1.22 MeV max.) and chemical properties, which emerged as a promising PET imaging agent. Objectives: This work aimed to develop and optimise a GMP-automated purification method for copper-61 produced in a cyclotron using a natural zinc liquid target. Methods: The automated purification process was performed using a commercially available Synthera ® Extension module (IBA, Louvain-la-Neuve, Belgium) using a three-column method: two extraction chromatographic resins and a strong anion exchange resin. The final product was evaluated using HPGe and ICP-MS analysis, to assess the radionuclidic and chemical purity of the final copper- 61 solution. Results: The automated purification process was completed within 1 h of processing time, with an average yield of 63.0 ± 15.0%, in a maximum volume of 5 mL. The radionuclidic purity of copper- 61 in the final solution was over 95% for 7 h after EOB. ICP-MS analysis revealed 4.8 ± 2.4 μg of natural zinc in the final purified sample, and the copper-61 molar activity was 230.5 ± 139.3 GBq/μmol. Conclusion: The described purification process allows for the production of a highly radionuclidically and chemically pure, GMP compliant copper-61 solution, ready to be used for the development of copper-61 based radiopharmaceuticals for routine clinical use.