**1. Introduction**

Radioisotopes (RIs), largely used worldwide in diagnostic imaging procedures in the fields of oncology, neurology and cardiology, are currently produced by medical cyclotron accelerators, starting from the irradiation of a specific target [1]. The growing number of cyclotrons of different energies installed worldwide has given a strong impulse to the production of conventional and emerging radionuclides for medical applications [2–14]. In particular, the great advantage of using medical cyclotrons is the possibility to produce the medical radionuclide of interest on site and on demand. Recently, the technological advancement in the radionuclides cyclotron-based production sector has encouraged the use of novel radioisotopes (mainly radiometals) in medical applications, for implementing the so-called personalized medicine approach. In particular, the strength of this approach relies on the possibility of selecting patients responding positively to the targeted treatment by performing a preliminary diagnostic imaging using the same radiopharmaceutical (theranostic approach) [15–18].

The most used RIs for PET (Positron Emission Tomography), such as <sup>18</sup>F and <sup>11</sup>C, are produced by liquid or gas targets, whereas the availability of radiometals through

**Citation:** Sciacca, G.; Martini, P.; Cisternino, S.; Mou, L.; Amico, J.; Esposito, J.; Gorgoni, G.; Cazzola, E. A Universal Cassette-Based System for the Dissolution of Solid Targets. *Molecules* **2021**, *26*, 6255. https:// doi.org/10.3390/molecules26206255

Academic Editor: Anne Roivainen

Received: 17 September 2021 Accepted: 14 October 2021 Published: 16 October 2021

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a cyclotron-based production requires the use of solid targets. This kind of target is generally composed by a pellet of the desired material, usually costly isotopically enriched material either in metal or oxide form, bonded to a backing plate or encapsulated in a holding shell [19–21]. Liquid target is also an alternative for radiometal production, certainly preferred in case of short half-life radionuclides, necessitating fast irradiation and processing chemistry [22]. However, limitations in the target concentration dissolved in the acidic solution lead to low production yield. In addition, this process is not exempt from issues related to the corrosiveness of the acidic target solution and possible gas formation [23–25]. On the other hand, despite the higher production yield achievable in choosing a solid target-based production, it requires important technological and structural investments for target manufacturing, specific target station, complex automated delivery systems and a dedicated post-irradiation target dissolution system [15,26]. This is in addition to the need to recover the costly enriched material.

Research and development on solid target technologies as well as commercial interest is very dynamic and is evolving very rapidly. Nevertheless, regarding target dissolution systems, to our knowledge mainly three devices are available to date on the market for solid target treatment (IBA-Pinctada® metal [27], ARTMS\_ QIS® [28], and Comecer-ALCEO [29]). These are all self-standing systems independent from the synthesis module. Each system is suited to the characteristics of the target provided by the same company and not adaptable to alternative solutions. In some cases (e.g., ALCEO retrofit [29]) the target can be processed directly at the irradiation site to avoid the transfer of the solid target to the radiochemistry lab. From this point of view, other research prototypes have been reported in the literature. Gelbart and Johnson have recently proposed a solid target system with in situ target dissolution featuring heating up to 100 ◦C, and gas bubbling agitation [30]. Similarly, Beaudoin et al. also developed an in-vault system solid target dissolution system [31].

Having the opportunity to work with a medical cyclotron already equipped with a solid target station and a pneumatic transfer system to the radiochemistry lab, the purpose of this work was the development of a simple and efficient solid target dissolution system compatible with commercial cassette-based synthesis modules. In this way it would be possible to perform the radiochemical processing, from the dissolution to the labelling, all at once using a single remotely controlled device. Keeping the system compact allows containing all the process in a single hot cell, lowering the probability of external and operator contamination. At the same time, this reduces the processing time and maximizes the recovery yield thanks to the absence of wasteful transfers from one system to another. The entire process, starting from dissolution up to radiopharmaceutical formulation, can be applied continuously.

In this regard, a specific solid target dissolution system has been developed in a collaboration between the LARAMED (LAboratory of RAdionuclides for MEDicine) group of the Italian National Institute for Nuclear Physics (INFN), at the Legnaro National Laboratories, and the Sacro Cuore Don Calabria Hospital (SCDCH), located at Negrar di Valpolicella, VR, Italy [32]. The idea of this new reactor originates from the INFN WO/2019/053570 patent [33], describing the technology for manufacturing solid targets by Magnetron Sputtering technique. Indeed, this patent also includes a dissolution reactor system based on open-bottomed vial, which was originally applied on a semi-automatic prototype system used for 99mTc and <sup>64</sup>Cu dissolution and recovery [8,34].

In this paper we describe the developed system and tests performed with three different irradiated targets to demonstrate the performance of the system under different dissolution conditions.
