The production of novel radionuclides is the first step towards the development of new effective radiopharmaceuticals, and the quality thereof directly affects the preclinical and clinical phases. In this review, novel radiometal production for medical applications is briefly elucidated. The production status of the imaging nuclide ⁴⁴Sc and the therapeutic β^--emitter nuclide ¹⁶¹Tb are compared to their more established counterparts, ⁶⁸Ga and ¹⁷⁷Lu according to their targetry, irradiation process, radiochemistry, and quality control aspects. The detailed discussion of these significant issues will help towards the future introduction of these promising radionuclides into drug manufacture for clinical application under Good Manufacturing Practice (GMP).

⁴⁴Sc has favorable properties for cancer diagnosis using Positron Emission Tomography (PET) making it a promising candidate for application in nuclear medicine. The implementation of its production with existing compact medical cyclotrons would mean the next essential milestone in the development of this radionuclide. While the production and application of ⁴⁴Sc has been comprehensively investigated, the development of specific targetry and irradiation methods is of paramount importance. As a result, the target was optimized for the ⁴⁴Ca(p,n)⁴⁴Sc nuclear reaction using CaO instead of CaCO₃, ensuring decrease in target radioactive degassing during irradiation and increased radionuclidic yield. Irradiations were performed at the research cyclotron at the Paul Scherrer Institute (~11 MeV, 50 µA, 90 min) and the medical cyclotron at the University of Bern (~13 MeV, 10 µA, 240 min), with yields varying from 200 MBq to 16 GBq. The development of targetry, chemical separation as well as the practical issues and implications of irradiations, are analyzed and discussed. As a proof-of-concept study, the ⁴⁴Sc produced at the medical cyclotron was used for a preclinical study using a previously developed albumin-binding prostate-specific membrane antigen (PSMA) ligand. This work demonstrates the feasibility to produce ⁴⁴Sc with high yields and radionuclidic purity using a medical cyclotron, equipped with a commercial solid target station.

Copper radioisotopes are generally employed for cancer imaging and therapy when firmly coordinated via a chelating agent coupled to a tumor-seeking vector. However, the biologically triggered Cu²⁺-Cu⁺ redox switching may constrain the in vivo integrity of the resulting complex, leading to demetallation processes. This unsought pathway is expected to be hindered by chelators bearing N, O, and S donors which appropriately complements the borderline-hard and soft nature of Cu²⁺ and Cu⁺. In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [⁶⁴Cu]Cu²⁺ and the stability of the [⁶⁴Cu]Cu-complexes thereof were evaluated. Among the chelators considered, the best results were obtained with 1,7-bis [2-(methylsulfanyl)ethyl]-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). DO2A2S was labelled at high molar activities in mild reaction conditions, and its [⁶⁴Cu]Cu²⁺ complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [⁶⁴Cu][Cu(DO2A2S)] revealed a behavior similar to other [⁶⁴Cu]Cu-labelled cyclen derivatives characterized by high liver and kidney uptake, which could either be ascribed to transchelation phenomena or metabolic processing of the intact complex.

The ISOLPHARM (ISOL technique for radioPHARMaceuticals) project is dedicated to the development of high purity radiopharmaceuticals exploiting the radionuclides producible with the future Selective Production of Exotic Species (SPES) Isotope Separation On-Line (ISOL) facility at the Legnaro National Laboratories of the Italian National Institute for Nuclear Physics (INFN-LNL). At SPES, a proton beam (up to 70 MeV) extracted from a cyclotron will directly impinge a primary target, where the produced isotopes are released thanks to the high working temperatures (2000 °C), ionized, extracted and accelerated, and finally, after mass separation, only the desired nuclei are collected on a secondary target, free from isotopic contaminants that decrease their specific activity. A case study for such project is the evaluation of the feasibility of the ISOL production of ⁶⁴Cu and ⁶⁷Cu using a zirconium germanide target, currently under development. The producible activities of ⁶⁴Cu and ⁶⁷Cu were calculated by means of the Monte Carlo code FLUKA, whereas dedicated off-line tests with stable beams were performed at LNL to evaluate the capability to ionize and recover isotopically pure copper.

⁴⁴Sc is a promising radionuclide for positron emission tomography (PET) in nuclear medicine. As a part of the implementation of a production site for ⁴⁴Sc, precise knowledge of the activity of the product is necessary. At the Paul Scherrer Institute (PSI) and the University of Bern (UniBE), ⁴⁴Sc is produced by enriched ⁴⁴CaO-target irradiation with a cyclotron. The two sites use different techniques for activity measurement, namely a dose calibrator at the PSI and a gamma-ray spectrometry system at UniBE and PSI. In this work, the ⁴⁴Sc was produced at the PSI, and samples of the product were prepared in dedicated containers for onsite measurements at PSI, UniBE, and the Institute of Radiation Physics (IRA) in Lausanne for precise activity measurement using primary techniques and for the calibration of the reference ionization chambers. An accuracy of 1% was obtained for the activity measurement, allowing for a precise calibration of the dose calibrator and gamma-ray spectrometry of the two production sites. Each production site now has the capability of measuring ⁴⁴Sc activity with an accuracy of 2%.