Over the last several years, the use of radiometals has gained increasing relevance in supporting the continuous development of new, complementary and more specific biological targeting agents. Radiopharmaceuticals labelled with radiometals from elements such as Tc, Zr, Y, Ga and Cu received increasing attention as they find application in both diagnostic SPECT and PET imaging techniques and radiotherapeutic purposes. Such interest stems from the wide variety of radionuclides available with distinct and complementary nuclear decay characteristics to choose from with unequalled specificity, but can also be explained by growing demand in targeted radionuclide therapy. As a result, as routine supply of these radiometals becomes mandatory, studies describing their production processes have expanded rapidly. Although most radiometals are traditionally provided by the irradiation of solid targets in specialized cyclotrons, recently developed techniques for producing radiometals through the irradiation of liquid targets have received growing attention due to compatibility with commonly available small medical cyclotrons, promising characteristics and encouraging results. Irradiating liquid targets to produce radiometals appears as a fast, reliable, convenient and cost-efficient alternative to the conventional solid target techniques, characterized by complex and time-consuming pre- and post-irradiation target handling. Production of radiometals in liquid targets incorporated to complete manufacturing processes for daily routine is already recognized as a viable alternative and complementary supply methodology to existing solid target based infrastructures to satisfy growing clinical demands. For instance, several sites already use the approach to produce⁶⁸Ga-radiopharmaceuticals for clinical use. This review article covers the production of common radiometals with clinical potential through the irradiation liquid targets. A comparison with the traditional solid target irradiation methods is presented when relevant.

An automated process for the production and purification of radiometals produced by irradiating liquid targets in a medical cyclotron, using a commercially available module, has been developed. The method is suitable for the production and purification of radiometals such as ⁶⁸Ga, ⁶⁴Cu and ⁶¹Cu through irradiation of liquid targets and is important for producing high specific activity radioisotopes with a substantial reduction in processing time and cost when compared with the solid target approach. The “liquid target” process also eliminates the need for pre- and post-irradiation target preparation and simplifies the transfer of irradiated material from target to hotcell. A ⁶⁸GaCl₃ solution can be obtained in about 35 min with an average yield of 73.9 ± 6.7% in less than 10 mL of volume. ⁶⁴CuCl₂ solutions can be obtained with an average yield of 81.2 ± 7.8% in about 1 h of processing time. A dedicated single-use disposable kit is used on a commercial IBA Synthera^® extension module.

PET imaging has gained significant momentum in the last few years, especially in the area of oncology, with an increasing focus on metal radioisotopes owing to their versatile chemistry and favourable physical properties. Copper-61 (t_1/2 = 3.33 h, 61% β⁺, E_max = 1.216 MeV) provides unique advantages versus the current clinical standard (i.e., gallium-68) even though, until now, no clinical amounts of ⁶¹Cu-based radiopharmaceuticals, other than thiosemicarbazone-based molecules, have been produced. This study aimed to establish a routine production, using a standard medical cyclotron, for a series of widely used somatostatin analogues, currently labelled with gallium-68, that could benefit from the improved characteristics of copper-61. We describe two possible routes to produce the radiopharmaceutical precursor, either from natural zinc or enriched zinc-64 liquid targets and further synthesis of [⁶¹Cu]Cu-DOTA-NOC, [⁶¹Cu]Cu-DOTA-TOC and [⁶¹Cu]Cu-DOTA-TATE with a fully automated GMP-compliant process. The production from enriched targets leads to twice the amount of activity (3.28 ± 0.41 GBq vs. 1.84 ± 0.24 GBq at EOB) and higher radionuclidic purity (99.97% vs. 98.49% at EOB). Our results demonstrate, for the first time, that clinical doses of ⁶¹Cu-based radiopharmaceuticals can easily be obtained in centres with a typical biomedical cyclotron optimised to produce ¹⁸F-based radiopharmaceuticals.

Following our previous work on the production of radiometals, such as⁶⁴Cu and⁶⁸Ga, through the irradiation of liquid targets using a medical cyclotron, we describe in this paper a technique to produce⁶¹Cu through the irradiation of natural zinc using a liquid target.